AKT1

Summary

AKT1 (AKT serine/threonine kinase 1, HGNC:391) is a protein-coding gene on chromosome 14q32.33, encoding RAC-alpha serine/threonine-protein kinase (P31749). AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. In precision oncology, AKT1 E17K confers sensitivity to Capivasertib + Fulvestrant in Her2-receptor Negative Breast Cancer (CIViC Level A); 10 further curated variant–drug associations are listed below.

This gene encodes one of the three members of the human AKT serine-threonine protein kinase family which are often referred to as protein kinase B alpha, beta, and gamma. These highly similar AKT proteins all have an N-terminal pleckstrin homology domain, a serine/threonine-specific kinase domain and a C-terminal regulatory domain. These proteins are phosphorylated by phosphoinositide 3-kinase (PI3K). AKT/PI3K forms a key component of many signalling pathways that involve the binding of membrane-bound ligands such as receptor tyrosine kinases, G-protein coupled receptors, and integrin-linked kinase. These AKT proteins therefore regulate a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. AKT proteins are recruited to the cell membrane by phosphatidylinositol 3,4,5-trisphosphate (PIP3) after phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) by PI3K. Subsequent phosphorylation of both threonine residue 308 and serine residue 473 is required for full activation of the AKT1 protein encoded by this gene. Phosphorylation of additional residues also occurs, for example, in response to insulin growth factor-1 and epidermal growth factor. Protein phosphatases act as negative regulators of AKT proteins by dephosphorylating AKT or PIP3. The PI3K/AKT signalling pathway is crucial for tumor cell survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating AKT1 which then phosphorylates and inactivates components of the apoptotic machinery. AKT proteins also participate in the mammalian target of rapamycin (mTOR) signalling pathway which controls the assembly of the eukaryotic translation initiation factor 4F (eIF4E) complex and this pathway, in addition to responding to extracellular signals from growth factors and cytokines, is disregulated in many cancers. Mutations in this gene are associated with multiple types of cancer and excessive tissue growth including Proteus syndrome and Cowden syndrome 6, and breast, colorectal, and ovarian cancers. Multiple alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 207 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Proteus syndrome (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 966 total — 4 pathogenic
• Phenotypes (HPO): 256
• Druggable target: yes — 30 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 11 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 9 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001382430

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:391
Approved symbol	AKT1
Name	AKT serine/threonine kinase 1
Location	14q32.33
Locus type	gene with protein product
Status	Approved
Aliases	RAC, PKB, PRKBA, AKT, RAC-alpha
Ensembl gene	ENSG00000142208
Ensembl biotype	protein_coding
OMIM	164730
Entrez	207

Gene structure

Transcript identifiers

Ensembl transcripts: 90 — 79 protein_coding, 8 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000349310, ENST00000402615, ENST00000407796, ENST00000544168, ENST00000553506, ENST00000553797, ENST00000554192, ENST00000554581, ENST00000554585, ENST00000554826, ENST00000554848, ENST00000555380, ENST00000555458, ENST00000555528, ENST00000556836, ENST00000557552, ENST00000610370, ENST00000649815, ENST00000682269, ENST00000683058, ENST00000683722, ENST00000684058, ENST00000714123, ENST00000714130, ENST00000855590, ENST00000855591, ENST00000855592, ENST00000855593, ENST00000855594, ENST00000855595, ENST00000855596, ENST00000855597, ENST00000855598, ENST00000855599, ENST00000855600, ENST00000939374, ENST00000939375, ENST00000939376, ENST00000939377, ENST00000939378, ENST00000939379, ENST00000939380, ENST00000939381, ENST00000939382, ENST00000939383, ENST00000939384, ENST00000939385, ENST00000939386, ENST00000939387, ENST00000939388, ENST00000939389, ENST00000939390, ENST00000959648, ENST00000959649, ENST00000959650, ENST00000959651, ENST00000959652, ENST00000959653, ENST00000959654, ENST00000959655, ENST00000959656, ENST00000959657, ENST00000959658, ENST00000959659, ENST00000959660, ENST00000959661, ENST00000959662, ENST00000959663, ENST00000959664, ENST00000959665, ENST00000959666, ENST00000959667, ENST00000959668, ENST00000959669, ENST00000959670, ENST00000959671, ENST00000959672, ENST00000959673, ENST00000959674, ENST00000959675, ENST00000959676, ENST00000959677, ENST00000959678, ENST00000959679, ENST00000959680, ENST00000959681, ENST00000959682, ENST00000959683, ENST00000959684, ENST00000959685

RefSeq mRNA: 7 — MANE Select: NM_001382430 NM_001014431, NM_001014432, NM_001382430, NM_001382431, NM_001382432, NM_001382433, NM_005163

CCDS: CCDS9994

Canonical transcript exons

ENST00000649815 — 15 exons

Exon	Start	End
ENSE00001296816	104773455	104773580
ENSE00001394660	104792598	104792722
ENSE00001614411	104773912	104773980
ENSE00002484709	104795484	104795748
ENSE00002485852	104769349	104770420
ENSE00002522726	104793127	104793304
ENSE00003473235	104776659	104776770
ENSE00003557545	104774938	104775003
ENSE00003561499	104772365	104772452
ENSE00003566907	104775652	104775799
ENSE00003619354	104772878	104773092
ENSE00003628636	104775076	104775207
ENSE00003642995	104780088	104780216
ENSE00003684409	104770745	104770847
ENSE00003724028	104773251	104773379

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 98.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.1218 / max 239.8198, expressed in 1812 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
145139	20.7359	1808
145138	6.3859	1730

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	98.05	gold quality
ganglionic eminence	UBERON:0004023	97.94	gold quality
endometrium epithelium	UBERON:0004811	97.88	gold quality
left adrenal gland	UBERON:0001234	97.72	gold quality
left adrenal gland cortex	UBERON:0035825	97.72	gold quality
right adrenal gland	UBERON:0001233	97.54	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.52	gold quality
lower esophagus	UBERON:0013473	97.50	gold quality
right adrenal gland cortex	UBERON:0035827	97.44	gold quality
ventricular zone	UBERON:0003053	97.42	gold quality
cortical plate	UBERON:0005343	97.28	gold quality
right coronary artery	UBERON:0001625	97.16	gold quality
gall bladder	UBERON:0002110	97.10	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.06	gold quality
body of stomach	UBERON:0001161	97.02	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.00	gold quality
ascending aorta	UBERON:0001496	96.99	gold quality
thoracic aorta	UBERON:0001515	96.99	gold quality
popliteal artery	UBERON:0002250	96.92	gold quality
tibial artery	UBERON:0007610	96.91	gold quality
aorta	UBERON:0000947	96.88	gold quality
adrenal cortex	UBERON:0001235	96.78	gold quality
descending thoracic aorta	UBERON:0002345	96.76	gold quality
adrenal gland	UBERON:0002369	96.76	gold quality
upper lobe of left lung	UBERON:0008952	96.68	gold quality
apex of heart	UBERON:0002098	96.67	gold quality
right lung	UBERON:0002167	96.58	gold quality
granulocyte	CL:0000094	96.48	gold quality
left coronary artery	UBERON:0001626	96.48	gold quality
right lobe of thyroid gland	UBERON:0001119	96.25	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.61

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
CDKN1B	Repression
FSTL1	Activation
MIA3	Activation
SLC2A1	Activation
STUB1	Activation

Upstream regulators (CollecTRI, top): AP1, APC, AR, ARID4B, BCL6, CEBPB, CREB1, CTCF, CTNNB1, CUX1, DLX3, DLX5, DNMT3B, EGR1, ELF1, EPAS1, ESR1, ESR2, EZH2, FAM170A, FOXC1, FOXC2, FOXN1, FOXO3, FOXO4, GLI1, HES1, HIF1A, HMGA2, IRF1, IRF3, IRF6, ITGAX, JUN, KMT2A, LHX8, MEF2A, MITF, MXD1, MYB

miRNA regulators (miRDB)

32 targeting AKT1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-6512-5P	98.76	69.29	1195
HSA-MIR-633	98.35	69.45	1167

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Binding of CTMP to PKBalpha reduces its activity by inhibiting phosphorylation on serine 473 and threonine 308. (PMID:11598301)
• regulated in platelets by collage receptor glycoprotein VI (PMID:11825911)
• Absence of mutations in the pleckstrin homology (PH) domain of protein kinase B (PKB/Akt) in malignant melanoma. (PMID:11828257)
• Immunohistochemical localization of phosphorylated AKT/PKB in multiple myeloma cells. (PMID:11902142)
• Akt enhances Mdm2-mediated ubiquitination and degradation of p53. (PMID:11923280)
• Identification of 14-3-3zeta as a protein kinase B/Akt substrate. (PMID:11956222)
• Phosphorylation of HDM2 by Akt, and protein binding (PMID:11960368)
• IGF-I protects the cells from apoptosis by blocking the activation of caspases, which may be responsible for the loss of FAK and Akt. (PMID:12011046)
• Akt promotes cell-cycle progression through the mechanisms of phosphorylation-dependent 14-3-3 binding to p27(Kip1) and cytoplasmic localization. (PMID:12042314)
• AKT activation delays radiation-induced apoptosis, allowing the DNA repair mechanism more time to remove cyclobutane thymine dimers (PMID:12070137)
• Different cellular localization, translocation, and insulin-induced phosphorylation of PKBalpha in HepG2 cells and hepatocytes (PMID:12112022)
• This study shows that activation of Akt by pervanadate or serum is associated with tyrosine phosphorylation of Akt. (PMID:12149249)
• 3’ phosphoinositide lipid-dependent translocation of PKB to the plasma membrane promotes serine 473 phosphorylation, which is, in turn, necessary for PDK1-mediated phosphorylation of threonine 308 and, consequentially, full PKB activation. (PMID:12167717)
• determination of high-resolution structure of the pleckstrin homology domain of bound to phosphatidylinositol (3,4,5)-trisphosphate (PMID:12176338)
• connective tissue growth factor induced fibronectin production, cell migration, and cytoskeletal rearrangement are associated with recruitment of Src and phosphorylation of p42/44 MAPK and protein kinase B (PMID:12218048)
• These data indicate that Akt may contribute to tumor-cell proliferation by phosphorylation and cytosolic retention of p27(kip1), thus relieving CDK2 from p27-induced inhibition. (PMID:12244301)
• Data show that activation of protein kinase B (PKB)/Akt, contributes to resistance to antiproliferative signals and breast cancer progression in part by impairing the nuclear import and action of p27. (PMID:12244302)
• Data show that cytoplasmic relocalization of p27(kip1), secondary to Akt-mediated phosphorylation, inactivates the growth inhibitory properties of p27(kip1) and sustains the proliferation of breast cancer cells. (PMID:12244303)
• PECAM-1 involvement through Akt/PKB activation in starvation-induced transendothelial migration of CD34+CD14+ circulating precursors (PMID:12393747)
• data demonstrate that Rho/ROCK pathway negatively regulates eNOS phosphorylation through inhibition of protein kinase B (PKB), whereas it downregulates eNOS expression independent of PKB (PMID:12446767)
• chemotherapeutic drugs exhibited their cytotoxic effects in part by down-regulating Akt signaling following TRADD expression (PMID:12446787)
• We conclude that normal HERG function in HEK293 cells requires basal activity of PKB. Our data represent the first evidence that PKB phosphorylation regulates K(+) channels. (PMID:12527373)
• Decreased phosphorylation of protein kinase B and erk1/erk2 in neutrophils from patients with myelodysplastic syndrome (PMID:12529294)
• This protein protects HL60 leukemia cells from TRAIL-induced apoptosis through a mechanism involving NF-kappaB activation and cFLIP(L) up-regulation. (PMID:12592338)
• Increased phosphorylation of this protein was observed in A431 clonal variants. (PMID:12722480)
• The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. (PMID:12727836)
• activation of Notch1 signaling mediates p53 function in HPV16 E6 and E7 cell transformation via phosphatidylinositol(PI3K)-PKB/Akt pathway (PMID:12768030)
• Akt is activated by adrenomedullin (PMID:12782295)
• AKT1 is regulated by JIP1 (PMID:12783873)
• results suggest that TRB3 promotes glucose output from liver under fasting conditions by binding to and interfering with Akt phosphorylation in response to residual insulin signaling (PMID:12791994)
• Akt regulates basic helix-loop-helix transcription factor-coactivator complex formation and activity during neuronal differentiation (PMID:12808085)
• phosphorylation by Akt regulates the antiapoptotic function of PED/PEA-15 at least in part by controlling the stability of PED/PEA-15 (PMID:12808093)
• There are clear indications of a cross-talk between PKB and important signaling molecules downstream of the T cell receptor that modulate the thresholds of thymocyte selection and T cell activation. (PMID:12874217)
• Akt has a pivotal role in the regulation of endometrial cancer cell survival through the up-regulation of a specific inhibitor of apoptosis protein (PMID:12888921)
• PI3K/Akt is essential for protecting human keratinocytes against UV-induced apoptosis, whereas NF-kappaB pathway provides little, if any, protective role (PMID:12952968)
• The activity of p38 MAP Kinase is regulated by AKT1 in neoplasms. (PMID:12972603)
• AKT is upregulated in prostate cancer and that expression is correlated with tumor progression (PMID:14520710)
• protein kinase B/AKT mediates regulation of survivin levels by integrins (PMID:14523021)
• AKT and MCAM are reciprocally regulated. (PMID:14534536)
• Data show that inhibition of protein kinase B (PKB) involves atypical protein kinase C zeta, which physically interacts with PKB in unstimulated cells. (PMID:14560023)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	akt1	ENSDARG00000099657
danio_rerio		ENSDARG00000111014
mus_musculus	Akt1	ENSMUSG00000001729
rattus_norvegicus	Akt1	ENSRNOG00000028629

Paralogs (5): PRKCQ (ENSG00000065675), AKT2 (ENSG00000105221), AKT3 (ENSG00000117020), PDPK1 (ENSG00000140992), PRKCD (ENSG00000163932)

Protein

Protein identifiers

RAC-alpha serine/threonine-protein kinase — P31749 (reviewed: P31749)

Alternative names: Protein kinase B, Protein kinase B alpha, Proto-oncogene c-Akt, RAC-PK-alpha

All UniProt accessions (8): P31749, A0A087WY56, A0A804HJM6, A0AAQ5BHJ3, A0AAQ5BHK3, B0LPE5, G3V2I6, G3V3X1

UniProt curated annotations — full annotation on UniProt →

Function. AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at ‘Ser-50’ negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT also regulates the storage of glucose in the form of glycogen by phosphorylating GSK3A at ‘Ser-21’ and GSK3B at ‘Ser-9’, resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT also regulates cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of ‘Ser-83’ decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at ‘Ser-939’ and ‘Thr-1462’, thereby activating the mTORC1 signaling pathway, and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. Also regulates the mTORC1 signaling pathway by catalyzing phosphorylation of CASTOR1 and DEPDC5. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Part of a positive feedback loop of mTORC2 signaling by mediating phosphorylation of MAPKAP1/SIN1, promoting mTORC2 activation. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at ‘Thr-24’, ‘Ser-256’ and ‘Ser-319’. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates ‘Ser-454’ on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of ‘Ser-273’, resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on ‘Ser-318’, which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor 1 (IGF1). AKT mediates the antiapoptotic effects of IGF1. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at ‘Thr-120’ and ‘Thr-387’ leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at ‘Thr-117’ and ‘Thr-384’ leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at ‘Ser-259’ and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity. Phosphorylates KAT6A at ‘Thr-369’ and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53. Phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility. Phosphorylates prohibitin (PHB), playing an important role in cell metabolism and proliferation. Phosphorylates CDKN1A, for which phosphorylation at ‘Thr-145’ induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation. Phosphorylates PCK1 at ‘Ser-90’, reducing the binding affinity of PCK1 to oxaloacetate and changing PCK1 into an atypical protein kinase activity using GTP as donor. Also acts as an activator of TMEM175 potassium channel activity in response to growth factors: forms the lysoK(GF) complex together with TMEM175 and acts by promoting TMEM175 channel activation, independently of its protein kinase activity. Acts as a regulator of mitochondrial calcium uptake by mediating phosphorylation of MICU1 in the mitochondrial intermembrane space, impairing MICU1 maturation. Acts as an inhibitor of tRNA methylation by mediating phosphorylation of the N-terminus of METTL1, thereby inhibiting METTL1 methyltransferase activity. In response to LPAR1 receptor pathway activation, phosphorylates Rabin8/RAB3IP which alters its activity and phosphorylates WDR44 which induces WDR44 binding to Rab11, thereby switching Rab11 vesicular function from preciliary trafficking to endocytic recycling.

Subunit / interactions. Interacts with BTBD10. Interacts with KCTD20. Interacts (via the C-terminus) with CCDC88A (via its C-terminus). Interacts with GRB10; the interaction leads to GRB10 phosphorylation thus promoting YWHAE-binding. Interacts with AGAP2 (isoform 2/PIKE-A); the interaction occurs in the presence of guanine nucleotides. Interacts with AKTIP. Interacts (via PH domain) with MTCP1, TCL1A and TCL1B. Interacts with CDKN1B; the interaction phosphorylates CDKN1B promoting 14-3-3 binding and cell-cycle progression. Interacts with MAP3K5 and TRAF6. Interacts with BAD, PPP2R5B, STK3 and STK4. Interacts (via PH domain) with SIRT1. Interacts with SRPK2 in a phosphorylation-dependent manner. Interacts with RAF1. Interacts with TRIM13; the interaction ubiquitinates AKT1 leading to its proteasomal degradation. Interacts with TNK2 and CLK2. Interacts (via the C-terminus) with THEM4 (via its C-terminus). Interacts with and phosphorylated by PDPK1. Interacts with PA2G4. Interacts with KIF14; the interaction is detected in the plasma membrane upon INS stimulation and promotes AKT1 phosphorylation. Interacts with FAM83B; activates the PI3K/AKT signaling cascade. Interacts with WDFY2 (via WD repeats 1-3). Forms a complex with WDFY2 and FOXO1. Interacts with FAM168A. Interacts with SYAP1 (via phosphorylated form and BSD domain); this interaction is enhanced in a mTORC2-mediated manner in response to epidermal growth factor (EGF) stimulation and activates AKT1. Interacts with PKHM3. Interacts with FKBP5/FKBP51; promoting interaction between Akt/AKT1 and PHLPP1, thereby enhancing dephosphorylation and subsequent activation of Akt/AKT1. Interacts with TMEM175; leading to formation of the lysoK(GF) complex. Acts as a negative regulator of the cGAS-STING pathway by mediating phosphorylation of CGAS during mitosis, leading to its inhibition. Interacts with SLC9D1 (when phosphorylated); the interaction facilitates the membrane translocation and activation of AKT1.

Subcellular location. Cytoplasm. Nucleus. Cell membrane. Mitochondrion intermembrane space.

Tissue specificity. Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Expressed in all human cell types so far analyzed. The Tyr-176 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages.

Post-translational modifications. O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1. O-GlcNAcylation at Ser-473 also probably interferes with phosphorylation at this site. Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity. Phosphorylation of the activation loop at Thr-308 by PDPK1/PDK1 is a prerequisite for full activation. Phosphorylation by mTORC2 in response to growth factors plays a key role in AKT1 activation: mTORC2 phosphorylates different sites depending on the context, such as Thr-450, Ser-473, Ser-477 or Thr-479, thereby facilitating subsequent phosphorylation of the activation loop by PDPK1/PDK1. Phosphorylation at Ser-473 by mTORC2 promotes ubiquitination and degradation by the proteasome. Also phosphorylated at Ser-477 and Thr-479 by CDK2, facilitating subsequent phosphorylation of the activation loop by PDPK1/PDK1. Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA. This phosphorylated form localizes to the cell membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation. Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1. Ser-473 phosphorylation is enhanced by interaction with AGAP2 isoform 2 (PIKE-A). Ser-473 phosphorylation is enhanced in focal cortical dysplasias with Taylor-type balloon cells. Ser-473 phosphorylation is enhanced by signaling through activated FLT3. Ser-473 is dephosphorylated by PHLPP. Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase. The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase. Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling. AIM2 acts as an inhibitor of AKT1 by inhibiting phosphorylation Ser-473: AIM2 acts both by inhibiting the activity of PRKDC/DNA-PK kinase and promoting dephosphorylation by PP2A phosphatase. Ubiquitinated; undergoes both ‘Lys-48’- and ‘Lys-63’-linked polyubiquitination. TRAF6-induced ‘Lys-63’-linked AKT1 ubiquitination is critical for phosphorylation and activation. When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated. When fully phosphorylated and translocated into the nucleus, undergoes ‘Lys-48’-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome. Also ubiquitinated by TRIM13 leading to its proteasomal degradation. Phosphorylated, undergoes ‘Lys-48’-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation. Ubiquitinated via ‘Lys-48’-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome. Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B. Acetylation results in reduced phosphorylation and inhibition of activity. Deacetylated at Lys-14 and Lys-20 by SIRT1. SIRT1-mediated deacetylation relieves the inhibition. Cleavage by caspase-3/CASP3. Cleaved at the caspase-3 consensus site Asp-462 during apoptosis, resulting in down-regulation of the AKT signaling pathway and decreased cell survival.

Disease relevance. Breast cancer (BC) [MIM:114480] A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Disease susceptibility is associated with variants affecting the gene represented in this entry. Colorectal cancer (CRC) [MIM:114500] A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. The gene represented in this entry may be involved in disease pathogenesis. Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer. Proteus syndrome (PROTEUSS) [MIM:176920] A highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Many features of Proteus syndrome overlap with other overgrowth syndromes. The disease is caused by variants affecting the gene represented in this entry. Cowden syndrome 6 (CWS6) [MIM:615109] A form of Cowden syndrome, a hamartomatous polyposis syndrome with age-related penetrance. Cowden syndrome is characterized by hamartomatous lesions affecting derivatives of ectodermal, mesodermal and endodermal layers, macrocephaly, facial trichilemmomas (benign tumors of the hair follicle infundibulum), acral keratoses, papillomatous papules, and elevated risk for development of several types of malignancy, particularly breast carcinoma in women and thyroid carcinoma in both men and women. Colon cancer and renal cell carcinoma have also been reported. Hamartomas can be found in virtually every organ, but most commonly in the skin, gastrointestinal tract, breast and thyroid. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Three specific sites, one in the kinase domain (Thr-308) and the two other ones in the C-terminal regulatory region (Ser-473 and Tyr-474), need to be phosphorylated for its full activation. Inhibited by pyrrolopyrimidine inhibitors like aniline triazole and spiroindoline.

Domain organisation. Binding of the PH domain to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane. PI(3,4,5)P3 is also required for phosphorylation at Thr-308 and subsequent activation. The PH domain mediates interaction with TNK2 and Tyr-176 is also essential for this interaction. The AGC-kinase C-terminal mediates interaction with THEM4.

Similarity. Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P31749-1	1	yes
P31749-2	2

RefSeq proteins (7): NP_001014431, NP_001014432, NP_001369359, NP_001369360, NP_001369361, NP_001369362, NP_005154 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR000961	AGC-kinase_C	Domain
IPR001849	PH_domain	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR017892	Pkinase_C	Domain
IPR034676	Akt1	Domain
IPR039026	PH_PKB	Domain

Pfam: PF00069, PF00169, PF00433

Enzyme classification (BRENDA):

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0007–0.64	11
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (112 total): strand 21, helix 20, mutagenesis site 20, modified residue 13, sequence conflict 8, binding site 6, glycosylation site 5, sequence variant 4, domain 3, turn 3, disulfide bond 2, region of interest 2, chain 1, site 1, cross-link 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

43 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1UNQ	X-RAY DIFFRACTION	0.98
1UNR	X-RAY DIFFRACTION	1.25
7MYX	X-RAY DIFFRACTION	1.39
1H10	X-RAY DIFFRACTION	1.4
8JOW	X-RAY DIFFRACTION	1.4
4GV1	X-RAY DIFFRACTION	1.49
1UNP	X-RAY DIFFRACTION	1.65
3QKL	X-RAY DIFFRACTION	1.9
7NH5	X-RAY DIFFRACTION	1.9
8UW9	X-RAY DIFFRACTION	1.9
2UVM	X-RAY DIFFRACTION	1.94
2UZR	X-RAY DIFFRACTION	1.94
8UW7	X-RAY DIFFRACTION	1.97
3CQW	X-RAY DIFFRACTION	2
4EKL	X-RAY DIFFRACTION	2
3MVH	X-RAY DIFFRACTION	2.01
7APJ	X-RAY DIFFRACTION	2.05
8UVY	X-RAY DIFFRACTION	2.11
6NPZ	X-RAY DIFFRACTION	2.12
6CCY	X-RAY DIFFRACTION	2.18
4EJN	X-RAY DIFFRACTION	2.19
3CQU	X-RAY DIFFRACTION	2.2
3QKM	X-RAY DIFFRACTION	2.2
8UW2	X-RAY DIFFRACTION	2.2
3QKK	X-RAY DIFFRACTION	2.3
6HHG	X-RAY DIFFRACTION	2.3
6HHJ	X-RAY DIFFRACTION	2.3
6S9W	X-RAY DIFFRACTION	2.3
7NH4	X-RAY DIFFRACTION	2.3
6BUU	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31749-F1	83.62	0.54

Antibody-complex structures (SAbDab): 7 — 7APJ, 8JOW, 8UVY, 8UW2, 8UW7, 8UW9, 8ZPU

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 462 (cleavage; by caspase-3); 274 (proton acceptor)

Ligand- & substrate-binding residues (6): 86; 156–164; 179; 14–19; 23–25; 53

Post-translational modifications (14): 14, 20, 124, 126, 129, 176, 308, 448, 450, 473, 474, 477, 479, 284

Disulfide bonds (2): 60–77, 296–310

Glycosylation sites (5): 126, 129, 305, 312, 473

Mutagenesis-validated functional residues (20):

Position	Phenotype
8	substantial reduction of ubiquitination, phosphorylation at t-308 and s-473, akt activation as well as igf1-induced memb
14	impairs interaction with ptdins(3,4,5)p3 and ptdins(3,4)p2.
14	substantial reduction of phosphorylation at t-308 and s-473, loss of akt activation, and loss of binding to pip3 as well
14	substantial reduction of ubiquitination, phosphorylation at t-308 and s-473, akt activation, loss of binding to pip3 as
17	loss of membrane localization; when associated with q-20.
20	substantial reduction of phosphorylation at t-308 and s-473, reduced akt activation, and reduced binding to pip3 as well
20	slight increase of phosphorylation at t-308 and s-473.
25	impairs interaction with ptdins(3,4,5)p3 and ptdins(3,4)p2.
76–78	abolished binding to cyclin-a, preventing phosphorylation by cdk2.
86	impairs interaction with ptdins(3,4,5)p3 and ptdins(3,4)p2.
176	significant loss of interaction with tnk2. loss of membrane localization. significant reduction in phosphorylation on se
179	abolished serine/threonine-protein kinase activity.
273–275	abolished binding to cyclin-a, preventing phosphorylation by cdk2.
305	reduces o-glcnac levels; reduces o-glcnac levels even more; when associated with a-312.
305	abolishes phosphorylation at thr-308.
308	5-fold activation and 18-fold activation; when associated with d-473.
312	reduces o-glcnac levels; reduces o-glcnac levels even more; when associated with a-305.
312	abolishes phosphorylation at thr-308.
473	7-fold activation and 25-fold activation; when associated with d-308.
474	55% inhibition of activation.

Function

Pathways and Gene Ontology

Reactome pathways

113 pathways

ID	Pathway
R-HSA-111447	Activation of BAD and translocation to mitochondria
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1358803	Downregulation of ERBB2:ERBB3 signaling
R-HSA-1445148	Translocation of SLC2A4 (GLUT4) to the plasma membrane
R-HSA-1474151	Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
R-HSA-165159	MTOR signalling
R-HSA-165181	Inhibition of TSC complex formation by AKT (PKB)
R-HSA-198323	AKT phosphorylates targets in the cytosol
R-HSA-198693	AKT phosphorylates targets in the nucleus
R-HSA-199418	Negative regulation of the PI3K/AKT network
R-HSA-203615	eNOS activation
R-HSA-211163	AKT-mediated inactivation of FOXO1A
R-HSA-354192	Integrin signaling
R-HSA-3769402	Deactivation of the beta-catenin transactivating complex
R-HSA-389357	CD28 dependent PI3K/Akt signaling
R-HSA-389513	Co-inhibition by CTLA4
R-HSA-392451	G beta:gamma signalling through PI3Kgamma
R-HSA-450385	Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA
R-HSA-450604	KSRP (KHSRP) binds and destabilizes mRNA
R-HSA-5218920	VEGFR2 mediated vascular permeability
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-5674400	Constitutive Signaling by AKT1 E17K in Cancer
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-6804757	Regulation of TP53 Degradation
R-HSA-6804758	Regulation of TP53 Activity through Acetylation
R-HSA-6804759	Regulation of TP53 Activity through Association with Co-factors
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-69202	Cyclin E associated events during G1/S transition
R-HSA-69656	Cyclin A:Cdk2-associated events at S phase entry
R-HSA-8849469	PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1

MSigDB gene sets: 1733 (showing top): PID_BCR_5PATHWAY, GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_LIPOPROTEIN_PARTICLE_STIMULUS, BIOCARTA_GCR_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_LIPID_MODIFICATION, BIOCARTA_PTEN_PATHWAY, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, REACTOME_SIGNALING_BY_NOTCH, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_FATTY_ACID_CATABOLIC_PROCESS

GO Biological Process (178): osteoblast differentiation (GO:0001649), maternal placenta development (GO:0001893), positive regulation of endothelial cell proliferation (GO:0001938), cell migration involved in sprouting angiogenesis (GO:0002042), complement receptor mediated signaling pathway (GO:0002430), sphingosine-1-phosphate receptor signaling pathway (GO:0003376), glycogen biosynthetic process (GO:0005978), regulation of glycogen biosynthetic process (GO:0005979), glucose metabolic process (GO:0006006), regulation of translation (GO:0006417), protein phosphorylation (GO:0006468), protein import into nucleus (GO:0006606), nitric oxide biosynthetic process (GO:0006809), activation-induced cell death of T cells (GO:0006924), inflammatory response (GO:0006954), response to oxidative stress (GO:0006979), signal transduction (GO:0007165), epidermal growth factor receptor signaling pathway (GO:0007173), G protein-coupled receptor signaling pathway (GO:0007186), cell population proliferation (GO:0008283), insulin receptor signaling pathway (GO:0008286), apoptotic mitochondrial changes (GO:0008637), response to heat (GO:0009408), gene expression (GO:0010467), negative regulation of autophagy (GO:0010507), positive regulation of endothelial cell migration (GO:0010595), positive regulation of gene expression (GO:0010628), negative regulation of long-chain fatty acid import across plasma membrane (GO:0010748), fibroblast migration (GO:0010761), positive regulation of fibroblast migration (GO:0010763), positive regulation of sodium ion transport (GO:0010765), positive regulation of glucose metabolic process (GO:0010907), regulation of neuron projection development (GO:0010975), negative regulation of macroautophagy (GO:0016242), phosphorylation (GO:0016310), protein ubiquitination (GO:0016567), peptidyl-serine phosphorylation (GO:0018105), peptidyl-threonine phosphorylation (GO:0018107), cytokine-mediated signaling pathway (GO:0019221), mammalian oogenesis stage (GO:0022605)

GO Molecular Function (22): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), protein serine/threonine/tyrosine kinase activity (GO:0004712), calmodulin binding (GO:0005516), ATP binding (GO:0005524), phosphatidylinositol-3,4,5-trisphosphate binding (GO:0005547), kinase activity (GO:0016301), enzyme binding (GO:0019899), kinase binding (GO:0019900), protein kinase binding (GO:0019901), nitric-oxide synthase regulator activity (GO:0030235), protein serine/threonine kinase inhibitor activity (GO:0030291), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), phosphatidylinositol-3,4-bisphosphate binding (GO:0043325), 14-3-3 protein binding (GO:0071889), potassium channel activator activity (GO:0099104), protein serine kinase activity (GO:0106310), TORC2 complex binding (GO:1904841), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (24): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial intermembrane space (GO:0005758), spindle (GO:0005819), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), cilium (GO:0005929), cell cortex (GO:0005938), microtubule cytoskeleton (GO:0015630), membrane (GO:0016020), lamellipodium (GO:0030027), vesicle (GO:0031982), protein-containing complex (GO:0032991), perinuclear theca (GO:0033011), ciliary basal body (GO:0036064), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), sperm glycocalyx (GO:0120238), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
PIP3 activates AKT signaling	3
Signal Transduction	2
Regulation of mRNA stability by proteins that bind AU-rich elements	2
Activation of BH3-only proteins	1
Intracellular signaling by second messengers	1
Downregulation of ERBB2 signaling	1
Membrane Trafficking	1
Metabolism of cofactors	1
MTOR signalling	1
Metabolism of nitric oxide: NOS3 activation and regulation	1
Regulation of gene expression in beta cells	1
Platelet Aggregation (Plug Formation)	1
TCF dependent signaling in response to WNT	1
Co-stimulation by CD28	1
Regulation of T cell activation by CD28 family	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
protein binding	4
protein kinase activity	3
cytoplasm	3
cellular process	2
intracellular membrane-bounded organelle	2
cell periphery	2
membrane-bounded organelle	2
plasma membrane bounded cell projection	2
cytoskeleton	2
sperm flagellum	2
ossification	1
cell differentiation	1
placenta development	1
developmental process involved in reproduction	1
anatomical structure development	1
maternal process involved in female pregnancy	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
sprouting angiogenesis	1
blood vessel endothelial cell migration	1
immune response-activating cell surface receptor signaling pathway	1
G protein-coupled receptor signaling pathway	1
sphingolipid mediated signaling pathway	1
glycogen metabolic process	1
glucan biosynthetic process	1
glycogen biosynthetic process	1
regulation of glucan biosynthetic process	1
regulation of glycogen metabolic process	1
hexose metabolic process	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
phosphorylation	1
protein modification process	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1

Protein interactions and networks

STRING

14324 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AKT1	CDC42	P21181	999
AKT1	HSP90AA1	P07900	996
AKT1	HSP90AB1	P08238	996
AKT1	PHLPP1	O60346	995
AKT1	CYBB	P04839	994
AKT1	NCF1	P14598	993
AKT1	NCF2	P19878	993
AKT1	ARRB2	P32121	993
AKT1	CYBA	P13498	992
AKT1	NCF4	Q15080	992
AKT1	PI3	P19957	991
AKT1	SMAD3	P84022	990
AKT1	AMOTL1	Q8IY63	986
AKT1	ARRB1	P49407	985
AKT1	ARHGDIA	P52565	982

IntAct

934 interactions, top by confidence:

A	B	Type	Score
CDC37	HSP90AA1	psi-mi:“MI:0914”(association)	0.900
AKT1	TCL1A	psi-mi:“MI:0915”(physical association)	0.830
AKT1	GSK3B	psi-mi:“MI:0407”(direct interaction)	0.830
AKT1	TCL1A	psi-mi:“MI:2364”(proximity)	0.830
AKT1	GSK3B	psi-mi:“MI:0914”(association)	0.830
PDPK1	AKT1	psi-mi:“MI:0217”(phosphorylation reaction)	0.820
MTOR	AKT1	psi-mi:“MI:0217”(phosphorylation reaction)	0.810
MTOR	AKT1	psi-mi:“MI:0915”(physical association)	0.810
PPP2CA	AKT1	psi-mi:“MI:0203”(dephosphorylation reaction)	0.760
AKT1	FOXO3	psi-mi:“MI:0915”(physical association)	0.750
THEM4	AKT1	psi-mi:“MI:0915”(physical association)	0.730
AKT1	THEM4	psi-mi:“MI:0914”(association)	0.730
SETDB1	AKT1	psi-mi:“MI:0915”(physical association)	0.720
AKT1	SETDB1	psi-mi:“MI:0403”(colocalization)	0.720
CDC37	AKT1	psi-mi:“MI:0915”(physical association)	0.710
VIM	AKT1	psi-mi:“MI:0915”(physical association)	0.710

BioGRID (1343): GSK3B (Biochemical Activity), AKT1 (Affinity Capture-Western), AKT1 (Reconstituted Complex), AKT1 (Affinity Capture-Western), ITPR1 (Affinity Capture-Western), AKT1 (PCA), ITPR1 (Biochemical Activity), ITPR3 (Biochemical Activity), AKT1 (Affinity Capture-Western), AKT1 (Affinity Capture-Western), PRKCZ (Affinity Capture-Western), GSK3B (Biochemical Activity), AKT1 (Reconstituted Complex), GRB10 (Biochemical Activity), BAD (Biochemical Activity)

ESM2 similar proteins: A2YNT8, A2ZAB5, A9TF79, O54833, O64812, O76484, P0C5D6, P19784, P20427, P21869, P28523, P31748, P31749, P31750, P43291, P43292, P47196, P49136, P49137, P49138, P49139, P68399, P68400, Q01314, Q02066, Q0D4J7, Q16644, Q2QY53, Q39192, Q39193, Q3SYZ2, Q3UMW7, Q5N942, Q66H84, Q6P9R2, Q6ZI44, Q6ZLP5, Q75H77, Q75LR7, Q75V57

Diamond homologs: A1A4I4, A1Z7T0, A1Z9X0, A7MBL8, A8KBH6, A8WUG4, F1M7Y5, O08874, O19111, O42632, P04409, P05126, P05128, P05129, P05130, P05696, P05771, P05772, P09215, P09216, P09217, P10102, P10829, P10830, P13677, P13678, P16054, P17252, P20444, P23298, P24583, P24723, P28867, P31748, P31749, P31750, P31751, P34722, P34885, P36582

SIGNOR signaling

200 interactions.

A	Effect	B	Mechanism
AKT1	“up-regulates activity”	PEA15	phosphorylation
AKT1	down-regulates	FOXO1	phosphorylation
TNF	up-regulates	AKT1
THEM4	down-regulates	AKT1	binding
AKT1	up-regulates	NOS3	phosphorylation
AKT1	“up-regulates quantity by stabilization”	MDM2	phosphorylation
AKT1	“up-regulates activity”	MDM2	phosphorylation
AKT1	unknown	YWHAZ	phosphorylation
AKT1	“up-regulates quantity by stabilization”	XIAP	phosphorylation
AKT1	down-regulates	CDKN1B	phosphorylation
AKT1	down-regulates	SMAD3	binding
AKT1	down-regulates	CHEK1	phosphorylation
AKT1	up-regulates	MDM2	phosphorylation
AKT1	down-regulates	ZFP36L1	phosphorylation
CSNK2A1	up-regulates	AKT1	phosphorylation
AKT1	down-regulates	GATA2	phosphorylation
PTPRF	down-regulates	AKT1	dephosphorylation
AKT1	up-regulates	GATA1	phosphorylation
AKT1	“down-regulates activity”	EZH2	phosphorylation
“prostaglandin E2”	up-regulates	AKT1	“chemical activation”
AKT1	down-regulates	RAF1	phosphorylation
AKT1	up-regulates	EP300	phosphorylation
AKT1	“up-regulates quantity by stabilization”	CDKN1A	phosphorylation
AKT1	up-regulates	BRCA1	phosphorylation
AKT1	down-regulates	AR	phosphorylation
AKT1	down-regulates	ZYX	phosphorylation
SHH	up-regulates	AKT1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 88 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Constitutive Signaling by AKT1 E17K in Cancer	8	49.0×	8e-10
Regulation of TP53 Expression and Degradation	6	45.1×	2e-07
VEGFR2 mediated vascular permeability	7	41.4×	3e-08
CD28 dependent PI3K/Akt signaling	7	40.0×	3e-08
Co-stimulation by CD28	7	38.6×	4e-08
Regulation of TP53 Degradation	8	34.0×	1e-08
Downregulation of ERBB2 signaling	6	33.1×	2e-06
Regulation of T cell activation by CD28 family	5	30.6×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
regulation of cellular response to heat	5	67.5×	9e-06
cellular response to heat	6	26.5×	5e-05
insulin receptor signaling pathway	6	17.1×	3e-04
cellular response to insulin stimulus	5	10.9×	7e-03
positive regulation of apoptotic process	10	7.3×	3e-04
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	7	7.0×	6e-03
protein phosphorylation	7	6.1×	9e-03
protein stabilization	7	6.0×	9e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

AKT1, also referred to as protein kinase B, is a known oncogene. AKT activation relies on the PI3K pathway, and is recognized as a critical node in the pathway. The E17 hotspot is the most characterized of AKT1 mutations, and has been shown to result in activation of the protein. Mutations in AKT1 have also been shown to confer resistance to allosteric kinase inhibitors in vitro.

From intOGen — cancer-driver classification: activating (oncogene-like) across 9 cancer types — ALL, BRCA, CESC, COADREAD, PRAD, PROSTATE, SARCNOS, UCEC, WDTC.

Clinical variants and AI predictions

ClinVar

966 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	398
Likely benign	468
Benign	56

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
13983	NM_001382430.1(AKT1):c.49G>A (p.Glu17Lys)	Pathogenic
40162	NM_001382430.1(AKT1):c.73C>T (p.Arg25Cys)	Pathogenic
40163	NM_001382430.1(AKT1):c.1303A>C (p.Thr435Pro)	Pathogenic
800567	NM_001382430.1(AKT1):c.49_50delinsAG (p.Glu17Arg)	Pathogenic

SpliceAI

2770 predictions. Top by Δscore:

Variant	Effect	Δscore
14:104770739:CCTCA:C	donor_loss	1.0000
14:104770740:CTCAC:C	donor_loss	1.0000
14:104770741:TCAC:T	donor_loss	1.0000
14:104770742:CACCT:C	donor_loss	1.0000
14:104770743:A:T	donor_loss	1.0000
14:104770744:CCTTG:C	donor_loss	1.0000
14:104770843:CTGAG:C	acceptor_gain	1.0000
14:104770844:TGAG:T	acceptor_gain	1.0000
14:104770848:C:CC	acceptor_gain	1.0000
14:104772360:CGCA:C	donor_loss	1.0000
14:104772362:CACC:C	donor_loss	1.0000
14:104772448:CAAGC:C	acceptor_gain	1.0000
14:104772450:AGC:A	acceptor_gain	1.0000
14:104772451:GC:G	acceptor_gain	1.0000
14:104772452:CC:C	acceptor_gain	1.0000
14:104772453:C:CC	acceptor_gain	1.0000
14:104772454:T:G	acceptor_loss	1.0000
14:104772872:CCTCA:C	donor_loss	1.0000
14:104772873:CTCA:C	donor_loss	1.0000
14:104772874:TCAC:T	donor_loss	1.0000
14:104772875:CACC:C	donor_loss	1.0000
14:104772877:C:G	donor_loss	1.0000
14:104772877:CCT:C	donor_gain	1.0000
14:104773269:A:AC	donor_gain	1.0000
14:104773270:G:C	donor_gain	1.0000
14:104773376:CCAG:C	acceptor_gain	1.0000
14:104773377:CAG:C	acceptor_gain	1.0000
14:104773377:CAGC:C	acceptor_gain	1.0000
14:104773378:AG:A	acceptor_gain	1.0000
14:104773378:AGCT:A	acceptor_loss	1.0000

AlphaMissense

3188 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:104770368:G:C	F472L	1.000
14:104770368:G:T	F472L	1.000
14:104770370:A:G	F472L	1.000
14:104770782:G:C	F442L	1.000
14:104770782:G:T	F442L	1.000
14:104770783:A:G	F442S	1.000
14:104770784:A:G	F442L	1.000
14:104772452:C:A	R391S	1.000
14:104772452:C:G	R391S	1.000
14:104772878:C:A	R391M	1.000
14:104772878:C:G	R391T	1.000
14:104772899:A:G	L384P	1.000
14:104772902:A:G	L383P	1.000
14:104772968:A:T	I361N	1.000
14:104772976:A:C	F358L	1.000
14:104772976:A:T	F358L	1.000
14:104772978:A:G	F358L	1.000
14:104772978:A:T	F358I	1.000
14:104772980:A:G	L357P	1.000
14:104773003:G:C	F349L	1.000
14:104773003:G:T	F349L	1.000
14:104773005:A:G	F349L	1.000
14:104773007:G:T	P348H	1.000
14:104773043:C:A	G336V	1.000
14:104773043:C:T	G336D	1.000
14:104773044:C:G	G336R	1.000
14:104773050:C:A	G334W	1.000
14:104773050:C:G	G334R	1.000
14:104773050:C:T	G334R	1.000
14:104773051:C:A	W333C	1.000

dbSNP variants (sampled 300 via entrez): RS1000039217 (14:104779740 G>A,T), RS1000140925 (14:104774776 C>T), RS1000252649 (14:104787524 G>A,T), RS1000525389 (14:104775902 C>T), RS1000559097 (14:104780007 C>T), RS1000734126 (14:104771841 C>T), RS1000863769 (14:104783027 C>T), RS1000874330 (14:104796359 A>G), RS1001235045 (14:104794952 CG>C), RS1001319770 (14:104787900 G>A,C), RS1001327430 (14:104783042 G>A), RS1001428587 (14:104790691 G>A), RS1001508858 (14:104788014 G>A), RS1001557147 (14:104779457 G>A,C), RS1001688773 (14:104787666 A>C,G)

Disease associations

OMIM: gene MIM:164730 | disease phenotypes: MIM:615109, MIM:114480, MIM:114500, MIM:167000, MIM:176920, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
Proteus syndrome	Definitive	Autosomal dominant
Cowden disease	Supportive	Autosomal dominant
Cowden syndrome 6	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Cowden syndrome 6	Limited	AD

Mondo (12): Cowden syndrome 6 (MONDO:0014048), hereditary breast carcinoma (MONDO:0016419), colorectal cancer (MONDO:0005575), ovarian cancer (MONDO:0008170), Proteus syndrome (MONDO:0008318), colon carcinoma (MONDO:0002032), breast adenocarcinoma (MONDO:0004988), ovarian neoplasm (MONDO:0021068), schizophrenia (MONDO:0005090), lung adenocarcinoma (MONDO:0005061), squamous cell carcinoma (MONDO:0005096), Cowden disease (MONDO:0016063)

Orphanet (7): Cowden syndrome (Orphanet:201), Hereditary breast cancer (Orphanet:227535), Rare ovarian cancer (Orphanet:213500), Proteus syndrome (Orphanet:744), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140), NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268)

HPO phenotypes

256 total (30 of 256 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000020	Urinary incontinence
HP:0000036	Abnormal penis morphology
HP:0000040	Long penis
HP:0000044	Hypogonadotropic hypogonadism
HP:0000053	Macroorchidism
HP:0000077	Abnormality of the kidney
HP:0000105	Enlarged kidney
HP:0000107	Renal cyst
HP:0000130	Abnormality of the uterus
HP:0000141	Amenorrhea
HP:0000158	Macroglossia
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000221	Furrowed tongue
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000276	Long face
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000360	Tinnitus
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000463	Anteverted nares
HP:0000464	Abnormality of the neck
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002223_64	HDL cholesterol	1.000000e-08
GCST002899_22	HDL cholesterol	8.000000e-09
GCST003524_5	Endometrial cancer	4.000000e-08
GCST003525_4	Endometrial endometrioid carcinoma	4.000000e-08
GCST004232_77	HDL cholesterol levels	3.000000e-08
GCST006611_139	HDL cholesterol	3.000000e-26
GCST010241_173	Apolipoprotein A1 levels	5.000000e-57
GCST010242_470	HDL cholesterol levels	4.000000e-38
GCST011816_9	Vitamin C levels	1.000000e-08
GCST90002398_227	Neutrophil count	7.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:1001514	endometrial endometrioid carcinoma
EFO:0004614	apolipoprotein A 1 measurement
EFO:0600003	vitamin C measurement
EFO:0004833	neutrophil count

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D002294	Carcinoma, Squamous Cell	C04.557.470.200.400; C04.557.470.700.400
D006223	Hamartoma Syndrome, Multiple	C04.445.435; C04.651.435; C04.700.435; C16.320.700.435
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D016715	Proteus Syndrome	C04.445.435.500; C04.651.435.500; C05.116.099.750; C05.660.585.620; C16.131.077.740; C16.131.621.585.620
C562840	Breast Cancer, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (10): CHEMBL2111353 (PROTEIN FAMILY), CHEMBL3038463 (PROTEIN COMPLEX), CHEMBL3885629 (PROTEIN FAMILY), CHEMBL4106175 (PROTEIN FAMILY), CHEMBL4282 (SINGLE PROTEIN), CHEMBL4523748 (PROTEIN-PROTEIN INTERACTION), CHEMBL5169068 (PROTEIN-PROTEIN INTERACTION), CHEMBL5169081 (PROTEIN-PROTEIN INTERACTION), CHEMBL6177912 (PROTEIN-PROTEIN INTERACTION), CHEMBL6177913 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

30 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 179,669 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2325741	CAPIVASERTIB	4	2,157
CHEMBL125	MILTEFOSINE	4	24,203
CHEMBL1448	NICLOSAMIDE	4	14,322
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL2177390	IPATASERTIB	3	2,231
CHEMBL2219422	AFURESERTIB	3	1,467
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL372764	PERIFOSINE	3	15,127
CHEMBL38380	FASUDIL	3	11,953
CHEMBL50	QUERCETIN	3	74,559
CHEMBL603469	LESTAURTINIB	3
CHEMBL4297188	MIRANSERTIB	2	769
CHEMBL1079175	MK-2206	2	3,008
CHEMBL1234354	PF-04691502	2	4,092
CHEMBL1355299	SULFAETHIDOLE	2	1,857
CHEMBL1908343	KALAFUNGIN	2
CHEMBL1980715	LAUROGUADINE	2	294
CHEMBL28509	EDELFOSINE	2	10,540
CHEMBL3137336	UPROSERTIB	2	1,624
CHEMBL4871106	RUPITASERTIB	2	282
CHEMBL521851	PICTILISIB	2
CHEMBL565612	SOTRASTAURIN	2
CHEMBL6246	ELLAGIC ACID	2
CHEMBL3544960	AT-13148	1
CHEMBL494089	GSK-690693	1
CHEMBL2016893	XL-418	1
CHEMBL3112866	SAR-260301	1
CHEMBL4751394	BAY-1125976	1
CHEMBL4802156	VEVORISERTIB	1
CHEMBL482967	CYC-116	1

Clinical evidence (CIViC)

Drug × variant × indication: 11 predictive associations from 13 curated evidence items; also 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
AKT1 E17K	Capivasertib + Fulvestrant	Her2-receptor Negative Breast Cancer	Sensitivity/Response	CIViC A	EID12181
PIK3CA Mutation OR PTEN Mutation OR AKT1 Mutation	Capivasertib + Fulvestrant	Breast Cancer	Sensitivity/Response	CIViC A	EID12020
AKT1 E17K	Capivasertib	Cancer	Sensitivity/Response	CIViC B	EID3039 +1
MTOR Mutation OR PIK3CA Mutation OR PTEN Mutation OR AKT1 Mutation OR AKT2 Mutation	Sapanisertib	Solid Tumor	Sensitivity/Response	CIViC B	EID12075
AKT1 E17K	Capivasertib	Breast Cancer	Sensitivity/Response	CIViC C	EID709
AKT1 Q79K	Dabrafenib	Melanoma	Resistance	CIViC C	EID6260
AKT1 E17K	Akt Inhibitor MK2206	Breast Cancer	Sensitivity/Response	CIViC D	EID231
AKT1 E17K	Uprosertib	Melanoma	Sensitivity/Response	CIViC D	EID707
AKT1 Q79K	Vemurafenib	Melanoma	Resistance	CIViC D	EID439 +1
AKT1 E17K	Vemurafenib	Melanoma	Resistance	CIViC D	EID4029
AKT1 Overexpression	Vemurafenib	Melanoma	Resistance	CIViC D	EID6259

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1130214	Efficacy	3	carboplatin;cisplatin	Lung Neoplasms
rs2494732	Efficacy	3	risperidone	Schizophrenia
rs2494752	Efficacy	3	carboplatin;cisplatin	Non-Small Cell Lung Carcinoma
rs3803300	Efficacy	3	risperidone	Schizophrenia

PharmGKB variants

10 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1130214	AKT1	3	2.00	1	carboplatin;cisplatin
rs2494732	AKT1	3	0.25	1	risperidone
rs2494750	AKT1		0.00	0
rs2494752	AKT1	3	2.00	1	carboplatin;cisplatin
rs2498786	AKT1		0.00	0
rs3803300	AKT1, ZBTB42	3	0.25	1	risperidone
rs3803304	AKT1		0.00	0
rs74090038	AKT1		0.00	0
rs2494743	AKT1		0.00	0
rs2498794	AKT1		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Akt (Protein kinase B, PKB) family

Most potent curated ligand interactions (21 total), top 21:

Ligand	Action	Affinity	Parameter
uprosertib	Inhibition	10.18	pKi
afuresertib	Inhibition	10.1	pKi
rizavasertib	Inhibition	9.8	pKi
NTQ1062	Inhibition	9.4	pIC50
rupitasertib	Inhibition	9.0	pIC50
ipatasertib	Inhibition	9.0	pIC50
compound 1 [PMID: 20005102]	Inhibition	9.0	pIC50
compound E22 [PMID: 31298542]	Inhibition	8.86	pIC50
GSK690693	Inhibition	8.66	pKd
Hu7691	Inhibition	8.4	pIC50
pifusertib	Inhibition	8.32	pIC50
MK-2206	Negative	8.3	pIC50
miransertib	Inhibition	8.3	pIC50
BAY1125976	Negative	8.28	pIC50
capivasertib	Inhibition	7.59	pIC50
Akt inhibitor VIII	Negative	7.24	pIC50
A-674563	Inhibition	7.12	pKd
engasertib	Inhibition	6.89	pIC50
MS15	Inhibition	6.1	pIC50
oridonin	Inhibition	5.08	pIC50
miltefosine	Inhibition	5.02	pIC50

Binding affinities (BindingDB)

2015 measured of 2610 human assays (2611 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-[4-[1-[2-(azetidin-1-yl)ethyl]-4-(4-fluoro-3-methylphenyl)imidazol-2-yl]piperidin-1-yl]-5-bromopyrimidin-4-amine	IC50	0.1 nM	US-9145392: Imidazole amines as modulators of kinase activity
6-[4-[1-[2-(azetidin-1-yl)ethyl]-4-(2-propan-2-yl-4-pyridinyl)imidazol-2-yl]piperidin-1-yl]-5-bromopyrimidin-4-amine	IC50	0.15 nM	US-9145392: Imidazole amines as modulators of kinase activity
5-{5-[(2S)-2-amino-3-(1H-indol-3-yl)propoxy]pyridin-3-yl}-3-methyl-1H-indazole	IC50	0.16 nM
(3Z)-5-(5-{[(2S)-2-amino-3-(1H-indol-3-yl)propyl]oxy}pyridin-3-yl)-3-(furan-2-ylmethylidene)-1,3-dihydro-2H-indol-2-one	IC50	0.17 nM
5-ethyl-6-[4-[4-(4-fluoro-3-methylphenyl)-1-[(1-methylazetidin-3-yl)methyl]imidazol-2-yl]piperidin-1-yl]pyrimidin-4-amine	IC50	0.3 nM	US-9145392: Imidazole amines as modulators of kinase activity
pyrazolopyridine analog, 9g	IC50	0.34 nM
3-amino-1-cyclopropyl-3-[4-[1-(difluoromethyl)-8-phenyl-[1,2,4]triazolo[4,3-a][1,5]naphthyridin-7-yl]phenyl]cyclobutan-1-ol	IC50	0.34 nM	US-8536193: Inhibitors of AKT activity
3-amino-3-[4-[1-(difluoromethyl)-8-phenyl-[1,2,4]triazolo[4,3-a][1,5]naphthyridin-7-yl]phenyl]-1-methylcyclobutan-1-ol	IC50	0.38 nM	US-8536193: Inhibitors of AKT activity
6-[4-[4-(3-chloro-4-fluorophenyl)-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidin-1-yl]-5-ethylpyrimidin-4-amine	IC50	0.4 nM	US-9145392: Imidazole amines as modulators of kinase activity
4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]-5-[4-(methylcarbamoyl)piperidin-1-yl]pyridine-2-carboxamide	IC50	0.4 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
6-[4-[1-[2-(ethylamino)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidin-1-yl]-5-propan-2-yloxypyrimidin-4-amine	IC50	0.52 nM	US-9145392: Imidazole amines as modulators of kinase activity
3-[(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propoxy]-5-{3-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl}pyridine	IC50	0.6 nM
3-[(2S)-2-amino-3-[(5-{1H-pyrazolo[3,4-c]pyridin-5-yl}pyridin-3-yl)oxy]propyl]-1H-indole	IC50	0.6 nM
Z/E=1:9	IC50	0.7 nM
4-amino-6-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[2-(2-methylpropylamino)ethyl]imidazol-2-yl]piperidin-1-yl]pyrimidine-5-carbonitrile	IC50	0.7 nM	US-9145392: Imidazole amines as modulators of kinase activity
4-amino-6-[4-[1-[2-(cyclopentylamino)ethyl]-4-(4-fluoro-3-methylphenyl)imidazol-2-yl]piperidin-1-yl]pyrimidine-5-carbonitrile	IC50	0.7 nM	US-9145392: Imidazole amines as modulators of kinase activity
3-amino-1-cyclopropyl-3-[4-[8-phenyl-1-(1,2,4-triazolidin-3-yl)-[1,2,4]triazolo[4,3-a][1,5]naphthyridin-7-yl]phenyl]cyclobutan-1-ol	IC50	0.7 nM	US-8536193: Inhibitors of AKT activity
3-amino-1-methyl-3-[4-[3-phenyl-9-(1H-pyrazol-5-yl)-5H-imidazo[1,2-c][1,3]benzoxazin-2-yl]phenyl]cyclobutan-1-ol	IC50	0.8 nM	US-8772283: Imidazo-oxazine compound or salt thereof
6-[4-[1-[2-(diethylamino)ethyl]-4-(4-fluoro-3-methylphenyl)imidazol-2-yl]piperidin-1-yl]-5-ethoxypyrimidin-4-amine	IC50	0.8 nM	US-9145392: Imidazole amines as modulators of kinase activity
4-amino-6-[4-[1-[2-(cyclopentylamino)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidin-1-yl]pyrimidine-5-carbonitrile	IC50	0.8 nM	US-9145392: Imidazole amines as modulators of kinase activity
5-{5-[(2S)-2-amino-3-(3-iodophenyl)propoxy]pyridin-3-yl}-3-methyl-1H-indazole	IC50	0.9 nM
Z/E=3:1	IC50	0.9 nM
4-amino-6-[4-[1-[2-(dimethylamino)ethyl]-4-(4-fluoro-3-methylphenyl)imidazol-2-yl]piperidin-1-yl]pyrimidine-5-carbonitrile	IC50	0.9 nM	US-9145392: Imidazole amines as modulators of kinase activity
5-(3-cyanoazetidin-1-yl)-4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	0.9 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
5-{5-[(2S)-2-amino-3-(1H-indol-3-yl)propoxy]pyridin-3-yl}-3-chloro-1H-indazole	IC50	1 nM
2-[2-(4-chloro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-1,3-diazinan-4-one	IC50	1 nM	US-9133168: Pyrimidine derivatives, preparation thereof, and pharmaceutical use thereof as akt(pkb) phosphorylation inhibitors
2-[2-(4,5-difluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-1,3-diazinan-4-one	IC50	1 nM	US-9133168: Pyrimidine derivatives, preparation thereof, and pharmaceutical use thereof as akt(pkb) phosphorylation inhibitors
2-[2-(4-chloro-5-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-1,3-diazinan-4-one	IC50	1 nM	US-9133168: Pyrimidine derivatives, preparation thereof, and pharmaceutical use thereof as akt(pkb) phosphorylation inhibitors
2-[2-(4,5-difluoro-2-methyl-2,3-dihydroindol-1-yl)-2-sulfanylideneethyl]-5-fluoro-6-morpholin-4-yl-1,3-diazinane-4-thione	IC50	1 nM	US-9133168: Pyrimidine derivatives, preparation thereof, and pharmaceutical use thereof as akt(pkb) phosphorylation inhibitors
6-[4-[1-[2-(azetidin-1-yl)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidin-1-yl]-5-chloropyrimidin-4-amine	IC50	1 nM	US-9145392: Imidazole amines as modulators of kinase activity
4-amino-6-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidin-1-yl]pyrimidine-5-carbaldehyde	IC50	1 nM	US-9145392: Imidazole amines as modulators of kinase activity
Jak Inhibitor 1	EC50	1 nM
CHEMBL3112850	IC50	1 nM	US-8993565: (6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives, preparation thereof and pharmaceutical use thereof as AKT(PKB) phosphorylation inhibitors
1-[4-[3-[3-[4-(1-aminocyclobutyl)phenyl]-2-(2-amino-3-pyridinyl)imidazo[4,5-b]pyridin-5-yl]phenyl]piperazin-1-yl]-2-methylpropan-1-one	KD	1.1 nM	US-8609688: Substituted imidazopyridinyl-aminopyridine compounds
5-{5-[(2S)-2-amino-3-(2-methoxynaphthalen-1-yl)propoxy]pyridin-3-yl}-3-methyl-1H-indazole	KI	1.1 nM
5-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(4-cyclopropylimidazol-1-yl)-N-[2-(4-cyclopropyl-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.1 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
(2S)-1-{[5-(3-methyl-1H-indazol-5-yl)pyridin-3-yl]oxy}-3-[3-(trifluoromethyl)phenyl]propan-2-amine	IC50	1.2 nM
5-{5-[(2S)-2-amino-3-[2-fluoro-5-(trifluoromethyl)phenyl]propoxy]pyridin-3-yl}-3-methyl-1H-indazole	IC50	1.2 nM
Z/E=1:1	IC50	1.2 nM
4-(4-cyclopropylimidazol-1-yl)-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-N-[2-[4-[(2S)-1,1,1-trifluoropropan-2-yl]-1,2,4-triazol-3-yl]-1,3-thiazol-4-yl]pyridine-2-carboxamide	IC50	1.2 nM	US-9908875: Apoptosis signal-regulating kinase inhibitors
4-(aminomethyl)-N-[(1S)-1-(4-chlorophenyl)ethyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide	IC50	1.2 nM	US-9492453: Protein kinase B inhibitors
3-amino-1-methyl-3-[4-[3-phenyl-9-(1H-pyrazol-4-yl)-5H-imidazo[1,2-c][1,3]benzoxazin-2-yl]phenyl]cyclobutan-1-ol	IC50	1.3 nM	US-8772283: Imidazo-oxazine compound or salt thereof
2-[4-(1-amino-3-hydroxy-3-methylcyclobutyl)phenyl]-3-phenyl-5H-imidazo[1,2-c][1,3]benzoxazine-8-carboxamide	IC50	1.3 nM	US-8772283: Imidazo-oxazine compound or salt thereof
5-{5-[(2S)-2-amino-3-(4-bromo-3-fluorophenyl)propoxy]pyridin-3-yl}-3-methyl-1H-indazole	IC50	1.3 nM
4-amino-6-[4-[1-[2-(azetidin-1-yl)ethyl]-4-(5-chloro-6-fluoro-3-pyridinyl)imidazol-2-yl]piperidin-1-yl]pyrimidine-5-carbonitrile	IC50	1.3 nM	US-9145392: Imidazole amines as modulators of kinase activity
4-(aminomethyl)-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide	IC50	1.3 nM	US-9492453: Protein kinase B inhibitors
3-amino-1-cyclopropyl-3-[4-(5-phenyl-8-oxa-3,6,10-triazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-4-yl)phenyl]cyclobutan-1-ol	IC50	1.4 nM	US-8772283: Imidazo-oxazine compound or salt thereof
3-amino-1-methyl-3-[4-(5-phenyl-8-oxa-3,6,10-triazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-4-yl)phenyl]cyclobutan-1-ol	IC50	1.4 nM	US-8772283: Imidazo-oxazine compound or salt thereof
(3E)-5-{5-[(2S)-2-amino-3-phenylpropoxy]pyridin-3-yl}-3-(furan-2-ylmethylidene)-2,3-dihydro-1H-indol-2-one	IC50	1.4 nM
5-chloro-6-[4-[1-[2-(methylamino)ethyl]-4-[2-(trifluoromethyl)-4-pyridinyl]imidazol-2-yl]piperidin-1-yl]pyrimidin-4-amine	IC50	1.4 nM	US-9145392: Imidazole amines as modulators of kinase activity

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	IC50	0.02	nM	CHEMBL5407182
10.64	IC50	0.023	nM	CHEMBL5406146
10.52	Ki	0.03	nM	CHEMBL523586
10.46	IC50	0.035	nM	CHEMBL5414576
10.44	IC50	0.036	nM	CHEMBL5398425
10.40	Ki	0.04	nM	CHEMBL469590
10.30	Ki	0.05	nM	CHEMBL520788
10.28	IC50	0.053	nM	CHEMBL5437264
10.27	IC50	0.054	nM	CHEMBL5428430
10.22	Ki	0.06	nM	CHEMBL470597
10.22	Ki	0.06	nM	CHEMBL496690
10.18	IC50	0.066	nM	UPROSERTIB
10.10	Ki	0.08	nM	AFURESERTIB
10.10	IC50	0.08	nM	AFURESERTIB
10.08	IC50	0.083	nM	CHEMBL5400934
10.04	IC50	0.091	nM	CHEMBL5408482
10.00	IC50	0.1	nM	CHEMBL3899716
10.00	Ki	0.1	nM	CHEMBL482536
9.92	IC50	0.12	nM	CHEMBL5438374
9.85	IC50	0.14	nM	CHEMBL5399312
9.82	IC50	0.15	nM	CHEMBL3966806
9.80	Ki	0.16	nM	A-443654
9.80	IC50	0.16	nM	A-443654
9.77	IC50	0.17	nM	CHEMBL210954
9.77	IC50	0.17	nM	CHEMBL573326
9.70	Kd	0.2	nM	CHEMBL3640738
9.70	Kd	0.2	nM	CHEMBL3640739
9.70	Kd	0.2	nM	CHEMBL3640740
9.70	Kd	0.2	nM	CHEMBL3640741
9.70	IC50	0.2	nM	Borussertib
9.70	Ki	0.2	nM	CHEMBL1099297
9.70	Ki	0.2	nM	CHEMBL1098938
9.66	IC50	0.22	nM	CHEMBL5411877
9.52	IC50	0.3	nM	CHEMBL3936990
9.52	IC50	0.3	nM	CHEMBL5405650
9.52	IC50	0.3	nM	CHEMBL5426352
9.52	IC50	0.3	nM	CHEMBL5748077
9.52	IC50	0.3	nM	CHEMBL5884975
9.52	IC50	0.3	nM	CHEMBL5842594
9.52	IC50	0.3	nM	CHEMBL6038712
9.52	IC50	0.3	nM	CHEMBL6009143
9.52	IC50	0.3	nM	CHEMBL5805382
9.52	IC50	0.3	nM	CHEMBL5740682
9.52	IC50	0.3	nM	CHEMBL5995978
9.52	IC50	0.3	nM	CHEMBL5753779
9.52	IC50	0.3	nM	CHEMBL5864230
9.52	IC50	0.3	nM	CHEMBL5823407
9.52	IC50	0.3	nM	CHEMBL5741074
9.52	IC50	0.3	nM	CHEMBL5866601
9.52	IC50	0.3	nM	CHEMBL6005110

PubChem BioAssay actives

2138 with measured affinity, of 6100 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-bromo-N-[(3S,4S)-4-(3-fluorophenyl)piperidin-3-yl]-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	<0.0001	uM
N-[(3S,4S)-4-(3,4,5-trifluorophenyl)piperidin-3-yl]-5,6-dihydropyrazolo[1,5-d][1,4]benzoxazepine-9-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	<0.0001	uM
3-bromo-N-[(3S,4S)-4-(3,4-difluorophenyl)piperidin-3-yl]-9-oxa-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	<0.0001	uM
3-chloro-N-[(3S,4S)-4-(3-fluorophenyl)piperidin-3-yl]-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	<0.0001	uM
3-bromo-N-[(3S,4S)-4-(3,5-difluorophenyl)piperidin-3-yl]-9-oxa-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	<0.0001	uM
3-chloro-N-[(3S,4S)-4-(3-fluorophenyl)piperidin-3-yl]-9-oxa-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	<0.0001	uM
N-(1-amino-3-phenylpropan-2-yl)-4-bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiophene-2-carboxamide	417617: Inhibition of AKT1	ki	<0.0001	uM
N-[(2S)-1-amino-3-(3-fluorophenyl)propan-2-yl]-4-bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiophene-2-carboxamide	417617: Inhibition of AKT1	ki	<0.0001	uM
3-bromo-N-[(3S,4S)-4-(3,4-difluorophenyl)piperidin-3-yl]-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	0.0001	uM
3-bromo-N-[(3S,4S)-4-(3,4,5-trifluorophenyl)piperidin-3-yl]-9-oxa-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	0.0001	uM
3-bromo-N-[(3S,4S)-4-[4-chloro-3-(trifluoromethyl)phenyl]piperidin-3-yl]-9-oxa-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	0.0001	uM
3-bromo-N-[(3S,4S)-4-(3,5-difluorophenyl)piperidin-3-yl]-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	0.0001	uM
3-chloro-N-[(3S,4S)-4-(3,4-difluorophenyl)piperidin-3-yl]-9-oxa-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	0.0001	uM
3-chloro-N-[(3S,4S)-4-(3,4,5-trifluorophenyl)piperidin-3-yl]-9-oxa-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	0.0001	uM
N-[(2S)-1-amino-3-phenylpropan-2-yl]-4-bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiophene-2-carboxamide	417617: Inhibition of AKT1	ki	0.0001	uM
N-[(2S)-1-amino-3-[2-(trifluoromethyl)phenyl]propan-2-yl]-4-bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiophene-2-carboxamide	417617: Inhibition of AKT1	ki	0.0001	uM
N-[(2S)-1-amino-3-[3-(trifluoromethyl)phenyl]propan-2-yl]-4-bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiophene-2-carboxamide	417617: Inhibition of AKT1	ki	0.0001	uM
N-[(2S)-1-amino-3-(4-fluorophenyl)propan-2-yl]-4-bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiophene-2-carboxamide	417617: Inhibition of AKT1	ki	0.0001	uM
N-[(2S)-1-amino-3-(3-fluorophenyl)propan-2-yl]-5-chloro-4-(4-chloro-1-methylpyrazol-5-yl)thiophene-2-carboxamide	1510816: Inhibition of Akt1 (unknown origin)	ki	0.0001	uM
N-[(2S)-1-amino-3-(3,4-difluorophenyl)propan-2-yl]-5-chloro-4-(4-chloro-1-methylpyrazol-5-yl)furan-2-carboxamide	1922466: Inhibition of AKT1 (unknown origin) using Sox-AKT-tide as substrate by continuous real time fluorescence detection based [gamma33P]ATP assay	ic50	0.0001	uM
(2S)-1-(1H-indol-3-yl)-3-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]propan-2-amine	1797345: Akt Kinase Assay from Article 10.1016/j.bmcl.2006.04.046: “Identification of a novel 3,5-disubstituted pyridine as a potent, selective, and orally active inhibitor of Akt1 kinase.”	ki	0.0002	uM
(3Z)-5-[5-[(2S)-2-amino-3-(1H-indol-3-yl)propoxy]-3-pyridinyl]-3-(furan-2-ylmethylidene)-1H-indol-2-one	1797513: Akt Kinase Assay from Article 10.1021/jm0701019: “Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase b/akt inhibitors with reduced hypotension.”	ic50	0.0002	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-6-[(2R)-2-amino-3-phenylpropoxy]-1-ethylimidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	477360: Inhibition of AKT	ki	0.0002	uM
N-[2-oxo-3-[1-[[4-(5-oxo-3-phenyl-6H-1,6-naphthyridin-2-yl)phenyl]methyl]piperidin-4-yl]-1H-benzimidazol-5-yl]prop-2-enamide	1849989: Inhibition of 6xHis-tagged full-length wild-type AKT1 (unknown origin) expressed in baculovirus infected Sf9 insect cells by HTRF assay	ic50	0.0002	uM
N-[(3S,4S)-4-(3,4-difluorophenyl)piperidin-3-yl]-3-ethyl-9-oxa-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	0.0002	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-6-[(1S)-3-amino-1-phenylpropoxy]-1-ethylimidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	477360: Inhibition of AKT	ki	0.0002	uM
5-[5-[(2S)-2-amino-3-(1H-indol-3-yl)propoxy]-3-pyridinyl]-3-[1-(furan-2-yl)-2-methylpropan-2-yl]-1,3-dihydroindol-2-one	267626: Inhibition of AKT1 in presence of 5 uM ATP	ic50	0.0002	uM
5-[5-[(2S)-2-amino-3-(1H-indol-3-yl)propoxy]-3-pyridinyl]-3-(furan-2-yl)-1,3-dihydroindol-2-one	436502: Inhibition of Akt	ic50	0.0002	uM
2-[[(1R)-1-(3-fluoro-7-methyl-4-oxo-2-piperidin-1-ylpyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoic acid	2035284: Inhibition of AKT phosphorylation in human T47D cells harboring PI3Kalpha H1047R mutant incubated for 24 hrs by AlphaLISA assay	ic50	0.0003	uM
N-[(3S,4S)-4-(3,5-difluorophenyl)piperidin-3-yl]-5,6-dihydropyrazolo[1,5-d][1,4]benzoxazepine-9-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	0.0003	uM
(2S)-1-(1H-indol-3-yl)-3-[[5-(3-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-3-pyridinyl]oxy]propan-2-amine	1797513: Akt Kinase Assay from Article 10.1021/jm0701019: “Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase b/akt inhibitors with reduced hypotension.”	ic50	0.0003	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-6-[(1R)-2-amino-1-phenylethoxy]-1-ethylimidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	477360: Inhibition of AKT	ki	0.0004	uM
(5R)-4-[(1S,6R)-5-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one	1912109: Inhibition of recombinant AKT1 (104 to 480 end residues) (unknown origin) catalytic domain expressed in Sf21 cells using peptide substrate incubated for 1 hr in presence of ATP by caliper off-chip mobility shift assay	ic50	0.0004	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	1801131: KinEASE Assay from Article 10.1021/cb500355c: “Discovery of inter-domain stabilizers-a novel assay system for allosteric akt inhibitors.”	ic50	0.0004	uM
3-bromo-N-[(3S,4S)-4-(4-chlorophenyl)piperidin-3-yl]-9-oxa-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	0.0004	uM
N-[(3S,4S)-4-(3,4-difluorophenyl)piperidin-3-yl]-5,6-dihydropyrazolo[1,5-d][1,4]benzoxazepine-9-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	0.0004	uM
N-[(3S,4S)-4-(3,4-difluorophenyl)piperidin-3-yl]-3-(2-hydroxyethyl)-9-oxa-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	0.0004	uM
N-[[(3S)-3-amino-1-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]methyl]-2,4-difluorobenzamide	492679: Inhibition of AKT1 after 90 mins by IMAP assay	ic50	0.0005	uM
(2S)-1-[[5-(3-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-3-pyridinyl]oxy]-3-[3-(trifluoromethyl)phenyl]propan-2-amine	1797513: Akt Kinase Assay from Article 10.1021/jm0701019: “Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase b/akt inhibitors with reduced hypotension.”	ic50	0.0006	uM
4-[(4-chlorophenyl)methoxymethyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amine	457296: Inhibition of PKB in human U87MG cells assessed as GSK3-beta phosphorylation by ELISA	ic50	0.0006	uM
(2S)-1-(1H-indol-3-yl)-3-[[5-(1H-pyrazolo[3,4-c]pyridin-5-yl)-3-pyridinyl]oxy]propan-2-amine	1797557: Akt Kinase Assay from Article 10.1016/j.bmc.2007.01.010: “Design and synthesis of pyridine-pyrazolopyridine-based inhibitors of protein kinase B/Akt.”	ic50	0.0006	uM
(4S)-5-[(1S,6R)-5-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-4-methyl-1,4-dihydropyrimido[4,5-d][1,3]oxazin-2-one	1912109: Inhibition of recombinant AKT1 (104 to 480 end residues) (unknown origin) catalytic domain expressed in Sf21 cells using peptide substrate incubated for 1 hr in presence of ATP by caliper off-chip mobility shift assay	ic50	0.0006	uM
(3Z)-5-[5-[(2S)-2-amino-3-phenylpropoxy]-3-pyridinyl]-3-(1H-pyrrol-2-ylmethylidene)-1H-indol-2-one	436502: Inhibition of Akt	ic50	0.0006	uM
(4S)-5-[(1R,5S)-8-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-4-methyl-1,4-dihydropyrimido[4,5-d][1,3]oxazin-2-one	1912109: Inhibition of recombinant AKT1 (104 to 480 end residues) (unknown origin) catalytic domain expressed in Sf21 cells using peptide substrate incubated for 1 hr in presence of ATP by caliper off-chip mobility shift assay	ic50	0.0006	uM
3-bromo-N-[(3S,4S)-4-[3-chloro-4-(trifluoromethyl)phenyl]piperidin-3-yl]-9-oxa-11-thia-5,6-diazatricyclo[8.3.0.02,6]trideca-1(10),2,4,12-tetraene-12-carboxamide;hydrochloride	2015817: Inhibition of AKT1 (unknown origin)	ic50	0.0006	uM
(2S)-2-(4-chlorophenyl)-1-[4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]piperazin-1-yl]-3-(propan-2-ylamino)propan-1-one	1831406: Binding affinity to wild-type human partial length AKT1 expressed in bacterial expression system assessed as residual binding level by Kinomescan method	kd	0.0006	uM
(5R)-4-[(1S,6R)-5-[(2S)-2-(4-chlorophenyl)-3-(cyclopropylamino)propanoyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one	1912109: Inhibition of recombinant AKT1 (104 to 480 end residues) (unknown origin) catalytic domain expressed in Sf21 cells using peptide substrate incubated for 1 hr in presence of ATP by caliper off-chip mobility shift assay	ic50	0.0007	uM
4-[(4-chlorophenyl)methyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amine	457296: Inhibition of PKB in human U87MG cells assessed as GSK3-beta phosphorylation by ELISA	ic50	0.0007	uM
(3Z)-5-[5-[(2S)-2-amino-3-(1H-indol-3-yl)propoxy]-3-pyridinyl]-3-[(5-methylfuran-2-yl)methylidene]-1H-indol-2-one	1797570: Akt Kinase Assay from Article 10.1016/j.bmcl.2006.04.005: “Discovery and SAR of oxindole-pyridine-based protein kinase B/Akt inhibitors for treating cancers.”	ic50	0.0007	uM
5-[5-[(2S)-2-amino-3-(1H-indol-3-yl)propoxy]-3-pyridinyl]-3-[2-methyl-1-(5-methylfuran-2-yl)propan-2-yl]-1,3-dihydroindol-2-one	267626: Inhibition of AKT1 in presence of 5 uM ATP	ic50	0.0007	uM

CTD chemical–gene interactions

979 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects expression, decreases expression, decreases degradation, decreases activity, affects reaction (+13 more)	142
Wortmannin	increases activity, increases reaction, decreases phosphorylation, decreases activity, decreases cleavage (+6 more)	51
Acetylcysteine	increases activity, increases phosphorylation, affects cotreatment, increases abundance, affects localization (+5 more)	40
Resveratrol	increases phosphorylation, affects cotreatment, affects reaction, decreases expression, decreases activity (+6 more)	38
Quercetin	increases reaction, increases activity, decreases phosphorylation, increases cleavage, increases expression (+7 more)	37
sodium arsenite	affects expression, increases expression, affects response to substance, increases activity, increases response to substance (+12 more)	34
Arsenic Trioxide	affects cotreatment, affects binding, decreases phosphorylation, increases reaction, decreases reaction (+10 more)	30
Hydrogen Peroxide	affects cotreatment, decreases phosphorylation, decreases reaction, increases phosphorylation, increases reaction (+8 more)	28
Curcumin	affects reaction, decreases reaction, increases activity, increases expression, decreases activity (+6 more)	26
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	affects binding, decreases reaction, affects cotreatment, decreases phosphorylation, affects reaction (+5 more)	23
bisphenol A	increases expression, decreases expression, increases phosphorylation, decreases reaction, affects reaction (+4 more)	20
Cadmium Chloride	decreases phosphorylation, increases activity, increases reaction, decreases reaction, decreases expression (+5 more)	19
Particulate Matter	affects cotreatment, increases abundance, decreases reaction, increases expression, affects reaction (+3 more)	18
Cisplatin	increases cleavage, increases expression, decreases reaction, decreases response to substance, increases phosphorylation (+5 more)	17
Estradiol	increases phosphorylation, increases reaction, affects cotreatment, decreases reaction, increases activity (+6 more)	17
Cadmium	affects cotreatment, affects reaction, increases reaction, decreases reaction, increases abundance (+2 more)	16
Doxorubicin	increases expression, decreases reaction, decreases phosphorylation, increases response to substance, increases reaction (+6 more)	16
Glucose	decreases reaction, decreases phosphorylation, affects reaction, affects cotreatment, increases phosphorylation (+3 more)	15
Oxygen	decreases expression, affects reaction, increases phosphorylation, decreases reaction, increases reaction (+4 more)	15
Fulvestrant	increases phosphorylation, affects cotreatment, decreases reaction	12
Tretinoin	decreases reaction, increases phosphorylation, increases reaction, decreases response to substance, affects cotreatment (+5 more)	12
Paclitaxel	increases cleavage, affects response to substance, decreases response to substance, increases activity, affects reaction (+6 more)	12
AKT activator SC79	increases phosphorylation, decreases phosphorylation, decreases reaction, increases abundance, affects phosphorylation (+2 more)	11
arsenite	increases reaction, increases activity, affects reaction, decreases reaction, affects cotreatment (+3 more)	11
U 0126	increases phosphorylation, decreases expression, decreases phosphorylation, decreases activity, affects cotreatment (+3 more)	11
Celecoxib	decreases response to substance, affects cotreatment, increases phosphorylation, decreases reaction, increases activity (+3 more)	11
Metformin	decreases reaction, increases reaction, affects cotreatment, increases expression, increases phosphorylation (+2 more)	11
Bortezomib	increases cleavage, increases activity, decreases expression, decreases reaction, decreases response to substance (+4 more)	10
Arsenic	increases expression, affects response to substance, affects expression, decreases expression, increases phosphorylation (+7 more)	10
Cannabidiol	increases phosphorylation, affects expression, increases expression, affects reaction, affects cotreatment (+3 more)	10

ChEMBL screening assays

1942 unique, capped per target: 1900 binding, 34 functional, 7 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3881290	Binding	Inhibition of PKB-PIF (unknown origin) using AKTide-2T peptide substrate and [gamma33P]-ATP incubated for 20 mins by scintillation counting method	Compositions comprising (S)-2-amino-1-(4-chlorophenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol as modulator of protein kinases
CHEMBL709030	Functional	Inhibition of Akt phosphorylation in LoVo cells	Synthesis and evaluation of 4-anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade. — Bioorg Med Chem Lett
CHEMBL4268857	ADMET	Inhibition of AKT phosphorylation in human NCI-H1975 cells at 10 uM after 24 hrs by Western blot analysis	Dichloroacetophenones targeting at pyruvate dehydrogenase kinase 1 with improved selectivity and antiproliferative activity: Synthesis and structure-activity relationships. — Bioorg Med Chem Lett

Cellosaurus cell lines

33 cell lines: 20 cancer cell line, 10 transformed cell line, 2 spontaneously immortalized cell line, 1 telomerase immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1344	KU-19-19	Cancer cell line	Male
CVCL_2929	HEC-50B	Cancer cell line	Female
CVCL_2960	IHH-4	Cancer cell line	Male
CVCL_3219	TMH-1	Cancer cell line	Male
CVCL_4Y59	Hec50Co	Cancer cell line	Female
CVCL_9827	MGH-U3	Cancer cell line	Male
CVCL_B1JD	Abcam HeLa AKT1 KO	Cancer cell line	Female
CVCL_B8B5	Abcam HCT 116 AKT1 KO	Cancer cell line	Male
CVCL_B8S9	Abcam MCF-7 AKT1 KO	Cancer cell line	Female
CVCL_B9D7	Abcam A-549 AKT1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

319 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03306446	PHASE4	UNKNOWN	Changing the coUrse of cRohn’s Disease With an Early Use of Adalimumab
NCT00114829	PHASE4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	PHASE4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	PHASE4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	PHASE4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00129870	PHASE4	TERMINATED	CONCEPT: Comparison of Oxaliplatin vs Conventional Methods With Calcium/Magnesium in First-Line Metastatic Colorectal Cancer
NCT00138060	PHASE4	COMPLETED	Toxicity/Benefit Ratio Optimization of Chemotherapy in Colorectal Cancer (CRC) Patients by Determination of Individual Genotypic Determinants
NCT00216424	PHASE4	TERMINATED	Capecitabine (Xeloda) and Radiation for Patients With Rectosigmoid Carcinoma
NCT00327093	PHASE4	TERMINATED	Elaboration of a Model for Predicting Efficacy of Monoclonal Antibodies (Cetuximab and Bevacizumab) in Patients With Colorectal Cancer and Liver Metastases
NCT00332943	PHASE4	COMPLETED	MR Colonography With Fecal Tagging. Barium vs. BariumFerumoxsil
NCT00441311	PHASE4	COMPLETED	Dissemination of Colorectal Cancer Screening to Primary Care Physicians
NCT00460837	PHASE4	WITHDRAWN	Comparison of Bowel Preparation in Virtual Colonoscopy (VC) - Patient Experience
NCT00473980	PHASE4	COMPLETED	Preoperative Non-steroidal Anti-inflammatory Drugs(NSAID) to Colorectal Cancer Patients
NCT00488904	PHASE4	COMPLETED	Omega-3 Fatty Acids and Postoperative Complications After Colorectal Surgery
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00502671	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) as Adjuvant Monotherapy in Patients With Colon Cancer.
NCT00559676	PHASE4	COMPLETED	Study of Biomarkers in Patients Undergoing Chemotherapy for Metastatic Colorectal Cancer
NCT00577031	PHASE4	COMPLETED	OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.
NCT00626054	PHASE4	COMPLETED	Comparison of Two Methods of Administration of a PEG Solution
NCT00812864	PHASE4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00868569	PHASE4	UNKNOWN	Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer
NCT00868816	PHASE4	COMPLETED	Oxaliplatine Based Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: 8 Cycles Versus 12 Cycles
NCT00874406	PHASE4	UNKNOWN	Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer
NCT00928928	PHASE4	COMPLETED	Oxidative Stress Markers in Open and Laparoscopic Colectomy for Cancer
NCT00942461	PHASE4	COMPLETED	Inflammatory Response in Laparoscopic and Open Colectomy
NCT01023633	PHASE4	UNKNOWN	OPTIMOX1 in Chinese mCRC Patients
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01315990	PHASE4	UNKNOWN	FOLFIRI in Combination With Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer Including a Regular Dermal Prophylaxis to Prevent Acneiforme Follicular Exanthema
NCT01493713	PHASE4	COMPLETED	Correlation Between RECIST, Morphologic Response by CT- Histopathologic Response in Hepatic Metastasis Secondary to Colorectal Cancer
NCT01609660	PHASE4	COMPLETED	Impact of Probiotics on the Intestinal Microbiota
NCT01641458	PHASE4	COMPLETED	Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
NCT01689792	PHASE4	COMPLETED	A Multi-centre Study Comparing the Polyp Detection Rate of Two Different Types of Bowel Preparation: a 2-litre Solution (MOVIPREP®) Versus a Hyperosmotic and Stimulant Combined Low Volume Bowel Preparation (Sodium Picosulfate and Magnesium Citrate)
NCT01695772	PHASE4	COMPLETED	A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer
NCT01695863	PHASE4	COMPLETED	Efficacy and Patient Satisfaction of Miralax and Gatorade Versus Movi Prep
NCT01706822	PHASE4	TERMINATED	Radial Reload Laparoscopic LAR Case Series
NCT01740947	PHASE4	TERMINATED	Does Administration of Antibiotics in Patients Undergoing Surgery for Colorectal Cancer Result in Less Complications and Better Prognosis?
NCT01831310	PHASE4	COMPLETED	Nutrition for Colorectal Cancer Patients and Neutrophil Functions
NCT01841294	PHASE4	UNKNOWN	NK Activity Modulation Induced by Intravenous Lidocaine During Colorectal Laparoscopic Surgery
NCT01959061	PHASE4	UNKNOWN	Efficacy and Safety of Raltitrexed-based Transarterial Chemoembolisation(TACE)for Colorectal Cancer Liver Metastases
NCT02032953	PHASE4	UNKNOWN	Enhancing the Anabolic Effect of Perioperative Nutrition With Insulin While Maintaining Normoglycemia