AKT3

Summary

AKT3 (AKT serine/threonine kinase 3, HGNC:393) is a protein-coding gene on chromosome 1q43-q44, encoding RAC-gamma serine/threonine-protein kinase (Q9Y243). AKT3 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, AKT3 E17K is associated with resistance to Vemurafenib in Melanoma (CIViC Level D); 4 further curated variant–drug associations are listed below.

The protein encoded by this gene is a member of the AKT, also called PKB, serine/threonine protein kinase family. AKT kinases are known to be regulators of cell signaling in response to insulin and growth factors. They are involved in a wide variety of biological processes including cell proliferation, differentiation, apoptosis, tumorigenesis, as well as glycogen synthesis and glucose uptake. This kinase has been shown to be stimulated by platelet-derived growth factor (PDGF), insulin, and insulin-like growth factor 1 (IGF1). Alternatively splice transcript variants encoding distinct isoforms have been described.

Source: NCBI Gene 10000 — RefSeq curated summary.

At a glance

• Gene–disease (curated): overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 38
• Clinical variants (ClinVar): 329 total — 13 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 51
• Druggable target: yes — 18 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 5 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005465

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:393
Approved symbol	AKT3
Name	AKT serine/threonine kinase 3
Location	1q43-q44
Locus type	gene with protein product
Status	Approved
Aliases	PKBG, RAC-gamma, PRKBG
Ensembl gene	ENSG00000117020
Ensembl biotype	protein_coding
OMIM	611223
Entrez	10000

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 11 protein_coding, 4 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay, 3 retained_intron

ENST00000263826, ENST00000336199, ENST00000366539, ENST00000366540, ENST00000463991, ENST00000490018, ENST00000491219, ENST00000492957, ENST00000550388, ENST00000552631, ENST00000672238, ENST00000672442, ENST00000672460, ENST00000672578, ENST00000672679, ENST00000673400, ENST00000673466, ENST00000679831, ENST00000680056, ENST00000680118, ENST00000681055, ENST00000681794

RefSeq mRNA: 4 — MANE Select: NM_005465 NM_001206729, NM_001370074, NM_005465, NM_181690

CCDS: CCDS31076, CCDS31077

Canonical transcript exons

ENST00000621586 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 99.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.1178 / max 200.9506, expressed in 1475 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
18366	6.6587	1383
18363	0.8141	382
18365	0.7449	355
18367	0.6822	273
18368	0.4114	187
18361	0.2638	95
18369	0.1638	75
18362	0.1284	46
18371	0.1269	55
18370	0.1236	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.26	gold quality
calcaneal tendon	UBERON:0003701	99.07	gold quality
embryo	UBERON:0000922	98.43	gold quality
ganglionic eminence	UBERON:0004023	98.43	gold quality
colonic epithelium	UBERON:0000397	97.70	gold quality
ventricular zone	UBERON:0003053	95.88	gold quality
popliteal artery	UBERON:0002250	94.02	gold quality
tibial artery	UBERON:0007610	94.01	gold quality
sural nerve	UBERON:0015488	93.59	gold quality
islet of Langerhans	UBERON:0000006	93.19	gold quality
smooth muscle tissue	UBERON:0001135	92.76	gold quality
right coronary artery	UBERON:0001625	92.63	gold quality
mucosa of stomach	UBERON:0001199	92.53	gold quality
aorta	UBERON:0000947	92.51	gold quality
left ovary	UBERON:0002119	91.50	gold quality
prefrontal cortex	UBERON:0000451	91.44	gold quality
left coronary artery	UBERON:0001626	91.40	gold quality
descending thoracic aorta	UBERON:0002345	91.33	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.04	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.84	gold quality
thoracic aorta	UBERON:0001515	90.81	gold quality
body of uterus	UBERON:0009853	90.79	gold quality
ascending aorta	UBERON:0001496	90.75	gold quality
anterior cingulate cortex	UBERON:0009835	90.58	gold quality
right lung	UBERON:0002167	90.57	gold quality
right frontal lobe	UBERON:0002810	90.34	gold quality
coronary artery	UBERON:0001621	90.22	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.21	gold quality
lower esophagus	UBERON:0013473	90.15	gold quality
cerebellar hemisphere	UBERON:0002245	90.12	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	34.68
E-ANND-3	yes	4.12

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting AKT3, 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-3140-3P	99.88	68.47	2069
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-501-3P	99.33	66.12	651
HSA-MIR-502-3P	99.33	66.12	651
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-502-5P	98.77	66.51	906
HSA-MIR-138-5P	98.43	70.49	1292
HSA-MIR-6861-5P	96.23	67.19	800
HSA-MIR-4444	92.67	67.92	56

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• results show that a defect in the ability of insulin to activate Akt-2 and -3 may explain the impaired insulin-stimulated glucose transport in insulin resistance (PMID:12663464)
• The regulation by Akt3 was found to be due to two specific regions in the Fra-1 regulatory sequence which match Sp1 consensus sites (PMID:12692267)
• The above results indicate that PKB-Ser-473 and FAK-Tyr phosphorylation stimulated by TGF-beta1 are both dependent on cell adhesion. (PMID:14637150)
• Targeted reduction of Akt3 activity with siRNA or by expressing active PTEN protein stimulated apoptotic signaling, which reduced cell survival by increasing apoptosis rates thereby inhibiting melanoma tumor development. (PMID:15466193)
• Rac1, PI3 kinase, and Akt3 have roles in an anti-apoptotic pathway triggered by ALS2 that antagonizes SOD1 mutant-induced motoneuronal cell death (PMID:15579468)
• activation of Akt signaling results in progression from adaptive to maladaptive cardiac hypertrophy (PMID:15698844)
• in breast cancer patients, Akt activation is associated with tumour proliferation and poor prognosis, particularly in the subset of patients with ErbB2-overexpressing tumours (PMID:15987444)
• AKT3 is highly expressed in 19 of 92 primary ovarian tumors, consistent with AKT3 playing a key role in the genesis of at least one subset of ovarian cancers. (PMID:17178867)
• AKT3 represents an excellent candidate for developmental human MIC and ACC, and we suggest that haploinsufficiency causes both postnatal MIC and ACC. (PMID:17668379)
• PKB[alpha] and/or PKB[gamma] and not PKB[beta] alone are involved in gemcitabine resistance mechanisms. (PMID:17895832)
• Akt3 and mutant V600E B-Raf cooperate to promote early melanoma development. (PMID:18451171)
• the first report of AKT mutations in melanoma, and the initial identification of an AKT3 mutation in any human cancer lineage (PMID:18813315)
• Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells (PMID:19261608)
• Findings indicate that AP-1 has an important function in pancreatic cancer cells and provide evidence for a previously unknown Akt-mediated mechanism of c-Jun activation. (PMID:19435822)
• Akt3 was located in the nucleus and nuclear membrane of human cell lines. (PMID:20018949)
• In breast cancer AKT3 amplifications and AKT1 and AKT2 deletions were seen by FISH (PMID:20102399)
• Our data suggest that Akt2 and Akt3 play an important role in the viability of human malignant glioma cells (PMID:20167810)
• We evaluated the presence of mutations in PIK3CA, AKT1, AKT2, AKT3, PTEN, and PDPK1 genes in 83 papillary thyroid carcinomas (PMID:20186503)
• Studies indicate that three different isoforms Akt1, Akt2, and Akt3 have distinct expression patterns and functions. (PMID:20398329)
• Mutant B-RAF melanoma cells ectopically expressing a constitutively activated form of Akt3 or endogenously expressing mutant Akt3 were protected from apoptosis induced by B-RAF knockdown or PLX4720 treatment. (PMID:20647317)
• No AKT3 E17K mutation was detected in the 73 squamous cell carcinomas of the lung (PMID:20980808)
• Expression of matrix metalloproteinase-13 is controlled by IL-13 via PI3K/Akt3 and PKC-delta in normal human dermal fibroblasts. (PMID:21191416)
• These findings suggest an important role for Akt3 in the regulation of RCAS1 and VEGF secretion in ovarian cancer cells. (PMID:21351097)
• We did not find any mutation in the GNAQ, AKT3, and PIK3R1 genes in various types of thyroid cancer. (PMID:21487925)
• Akt3 was required for anchorage-independent growth of transformed astrocytes and human glioma cells (PMID:21507933)
• Transcriptional activation of the Akt3 pathway indicates that it is involved in lumbar disc degeneration. (PMID:21590431)
• Our data demonstrate that Akt1 and notably Akt3 regulate proliferation, survival, migration and EGF-mediated signal transduction in NSCLC-derived DTC (PMID:21777670)
• Akt3 plays an important and distinct role in platelet activation and in thrombosis. (PMID:21821713)
• The prognostic impact of Akt (Akt1) phosphorylated at threonine308 and serine473, Akt2, Akt3, PI3K and PTEN, alone and in coexpression with ER and PgR in non-gastrointestinal stromal tumor soft tissue sarcomas. (PMID:22107784)
• Resveratrol down-regulates the protein cyclin D1 and, in a concentration dependent manner, the phosphorylation levels of protein kinase B and glycogen synthase kinase-3beta in OVCAR-3 ovarian cancer cells. (PMID:22234583)
• In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2. (PMID:22262409)
• This study identifies a trisomy on chromosome 1q, which encompasses AKT3, and a separate activating AKT3 somatic mutation in patients with the developmental brain disorder hemimegalencephaly. (PMID:22500628)
• Exome sequencing and mass spectrometry analysis in paired brain-blood samples from individuals with hemimegalencephaly (20 cases) identified de novo somatic mutations in 30% of affected individuals in the PIK3CA, AKT3 and MTOR genes. (PMID:22729223)
• identified mutations in AKT3, PIK3R2 and PIK3CA in 11 unrelated families with megalencephaly-capillary malformation and megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndromes (PMID:22729224)
• AKT3, ANGPTL4, eNOS3, and VEGFA associations with high altitude sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau. (PMID:22729570)
• AKT isoforms 1 and 3 promote basal as well as EGF-induced trophoblast migration. (PMID:23303682)
• Akt3 coimmunoprecipitates with Ago2. (PMID:23603119)
• Duplication of AKT3 causes macrocephaly. (PMID:23794269)
• Induction of transgenic Akt3 constitutively activates pathways for survival by counteracting motor neuronal degeneration in patients with amyotrophic lateral sclerosis. (PMID:23873136)
• detected and measured all three AKT isoforms 1, 2 and 3 to enable the study of the multiple and variable roles that these isoforms play in AKT breast tumorigenesis (PMID:23929892)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	akt3a	ENSDARG00000104810
mus_musculus	Akt3	ENSMUSG00000019699
rattus_norvegicus	Akt3	ENSRNOG00000021497

Paralogs (5): PRKCQ (ENSG00000065675), AKT2 (ENSG00000105221), PDPK1 (ENSG00000140992), AKT1 (ENSG00000142208), PRKCD (ENSG00000163932)

Protein

Protein identifiers

RAC-gamma serine/threonine-protein kinase — Q9Y243 (reviewed: Q9Y243)

Alternative names: Protein kinase Akt-3, Protein kinase B gamma, RAC-PK-gamma, STK-2

All UniProt accessions (11): A0A5F9ZGY0, A0A5F9ZGZ4, A0A5F9ZHA9, A0A5F9ZHU3, A0A5K1VW74, A0A7P0T872, A0A7P0T8T9, A0A7P0TB29, A0A7P0TB32, A0A7P0TBJ6, Q9Y243

UniProt curated annotations — full annotation on UniProt →

Function. AKT3 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. AKT3 is the least studied AKT isoform. It plays an important role in brain development and is crucial for the viability of malignant glioma cells. AKT3 isoform may also be the key molecule in up-regulation and down-regulation of MMP13 via IL13. Required for the coordination of mitochondrial biogenesis with growth factor-induced increases in cellular energy demands. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis.

Subunit / interactions. Interacts (via PH domain) with TCL1A; this enhances AKT3 phosphorylation and activation. Interacts with TRAF6. Interacts with KCTD20. Interacts with BTBD10.

Subcellular location. Nucleus. Cytoplasm. Membrane.

Tissue specificity. In adult tissues, it is highly expressed in brain, lung and kidney, but weakly in heart, testis and liver. In fetal tissues, it is highly expressed in heart, liver and brain and not at all in kidney.

Post-translational modifications. Phosphorylation on Thr-305 and Ser-472 is required for full activity. Phosphorylation of the activation loop at Thr-305 by PDPK1/PDK1 is a prerequisite for full activation. Phosphorylation at Ser-472 by mTORC2 in response to growth factors plays a key role in AKT1 activation by facilitating subsequent phosphorylation of the activation loop by PDPK1/PDK1. Ubiquitinated. When fully phosphorylated and translocated into the nucleus, undergoes ‘Lys-48’-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome. O-GlcNAcylation at Thr-302 and Thr-309 inhibits activating phosphorylation at Thr-305 via disrupting the interaction between AKT and PDPK1/PDK1.

Disease relevance. AKT3 is a key modulator of several tumors like melanoma, glioma and ovarian cancer. Active AKT3 increases progressively during melanoma tumor progression with highest levels present in advanced-stage metastatic melanomas. Promotes melanoma tumorigenesis by decreasing apoptosis. Plays a key role in the genesis of ovarian cancers through modulation of G2/M phase transition. With AKT2, plays a pivotal role in the biology of glioblastoma. Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (MPPH2) [MIM:615937] A syndrome characterized by megalencephaly, hydrocephalus, and polymicrogyria; polydactyly may also be seen. There is considerable phenotypic similarity between this disorder and the megalencephaly-capillary malformation syndrome. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Two specific sites, one in the kinase domain (Thr-305) and the other in the C-terminal regulatory region (Ser-472), need to be phosphorylated for its full activation. IGF-1 leads to the activation of AKT3, which may play a role in regulating cell survival.

Domain organisation. Binding of the PH domain to the phosphatidylinositol 3-kinase alpha (PI(3)K) results in its targeting to the plasma membrane.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y243-1	1, PKB gamma	yes
Q9Y243-2	2, PKB gamma 1

RefSeq proteins (4): NP_001193658, NP_001357003, NP_005456, NP_859029 (=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
IPR034675	Akt3	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 (42 total): strand 8, mutagenesis site 6, modified residue 4, sequence variant 4, glycosylation site 3, domain 3, helix 3, disulfide bond 2, binding site 2, initiator methionine 1, chain 1, splice variant 1, sequence conflict 1, turn 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8ZXW	X-RAY DIFFRACTION	1.33
2X18	X-RAY DIFFRACTION	1.46

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y243-F1	82.42	0.52

Antibody-complex structures (SAbDab): 1 — 8ZXW

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 (1): 271 (proton acceptor)

Ligand- & substrate-binding residues (2): 154–162; 177

Post-translational modifications (4): 305, 447, 472, 2

Disulfide bonds (2): 59–76, 293–307

Glycosylation sites (3): 302, 309, 472

Mutagenesis-validated functional residues (6):

Position	Phenotype
305	no activation after pervanadate treatment.
305	2-fold increase of phosphorylation steady state level, no activation after pervanadate treatment.
447	no effect.
472	67% decrease of activity after pervanadate treatment.
472	1.4-fold increase of phosphorylation steady state level, 50% decrease of activity after pervanadate treatment.

Function

Pathways and Gene Ontology

Reactome pathways

83 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-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-211163	AKT-mediated inactivation of FOXO1A
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-5218920	VEGFR2 mediated vascular permeability
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-5674400	Constitutive Signaling by AKT1 E17K in Cancer
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-69202	Cyclin E associated events during G1/S transition
R-HSA-69656	Cyclin A:Cdk2-associated events at S phase entry
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs
R-HSA-8941332	RUNX2 regulates genes involved in cell migration
R-HSA-8948751	Regulation of PTEN stability and activity
R-HSA-9607240	FLT3 Signaling
R-HSA-9614399	Regulation of localization of FOXO transcription factors
R-HSA-9634638	Estrogen-dependent nuclear events downstream of ESR-membrane signaling
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-9755779	SARS-CoV-2 targets host intracellular signalling and regulatory pathways
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity
R-HSA-109581	Apoptosis

MSigDB gene sets: 744 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, AP1_01, HNF3ALPHA_Q6, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, TGCACTT_MIR519C_MIR519B_MIR519A, LFA1_Q6, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, AAGCCAT_MIR135A_MIR135B, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT

GO Biological Process (20): positive regulation of endothelial cell proliferation (GO:0001938), signal transduction (GO:0007165), insulin receptor signaling pathway (GO:0008286), regulation of mitochondrion organization (GO:0010821), positive regulation of TOR signaling (GO:0032008), intracellular signal transduction (GO:0035556), negative regulation of apoptotic process (GO:0043066), positive regulation of blood vessel endothelial cell migration (GO:0043536), positive regulation of angiogenesis (GO:0045766), positive regulation of cell size (GO:0045793), brain morphogenesis (GO:0048854), homeostasis of number of cells within a tissue (GO:0048873), positive regulation of cell migration involved in sprouting angiogenesis (GO:0090050), negative regulation of PERK-mediated unfolded protein response (GO:1903898), positive regulation of vascular endothelial cell proliferation (GO:1905564), positive regulation of artery morphogenesis (GO:1905653), negative regulation of cellular senescence (GO:2000773), obsolete mitochondrial genome maintenance (GO:0000002), protein phosphorylation (GO:0006468), positive regulation of cell migration (GO:0030335)

GO Molecular Function (8): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (9): nucleoplasm (GO:0005654), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), cilium (GO:0005929), ciliary basal body (GO:0036064), nucleus (GO:0005634), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
PIP3 activates AKT signaling	3
Regulation of TP53 Activity	2
Activation of BH3-only proteins	1
Intracellular signaling by second messengers	1
Downregulation of ERBB2 signaling	1
Signal Transduction	1
MTOR signalling	1
Regulation of gene expression in beta cells	1
Co-stimulation by CD28	1
Regulation of T cell activation by CD28 family	1
G-protein beta:gamma signalling	1
VEGFA-VEGFR2 Pathway	1
Transcriptional Regulation by TP53	1
PI3K/AKT Signaling in Cancer	1
Regulation of TP53 Expression and Degradation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular anatomical structure	2
protein kinase activity	2
cytoplasm	2
intracellular membrane-bounded organelle	2
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
mitochondrion organization	1
regulation of organelle organization	1
TOR signaling	1
regulation of TOR signaling	1
positive regulation of intracellular signal transduction	1
signal transduction	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
positive regulation of endothelial cell migration	1
blood vessel endothelial cell migration	1
regulation of blood vessel endothelial cell migration	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
regulation of cell size	1
brain development	1
animal organ morphogenesis	1
tissue homeostasis	1
homeostasis of number of cells	1
cell migration involved in sprouting angiogenesis	1
positive regulation of blood vessel endothelial cell migration	1
regulation of cell migration involved in sprouting angiogenesis	1
PERK-mediated unfolded protein response	1
negative regulation of endoplasmic reticulum unfolded protein response	1

Protein interactions and networks

STRING

3250 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AKT3	PHLPP2	Q6ZVD8	964
AKT3	PHLPP1	O60346	936
AKT3	PIK3CA	P42336	839
AKT3	PIK3R1	P27986	769
AKT3	PTEN	P60484	766
AKT3	PLEK2	Q9NYT0	741
AKT3	PRKDC	P78527	736
AKT3	PIK3R3	Q92569	733
AKT3	PIK3CG	P48736	733
AKT3	PLEK	P08567	723
AKT3	TSC2	P49815	685
AKT3	MDM2	Q00987	676
AKT3	RICTOR	Q6R327	658
AKT3	PIK3R2	O00459	657
AKT3	PIK3CB	P42338	636

IntAct

28 interactions, top by confidence:

A	B	Type	Score
CDC37	AKT3	psi-mi:“MI:0915”(physical association)	0.690
AKT1	AKT2	psi-mi:“MI:0914”(association)	0.640
CASP3	AKT3	psi-mi:“MI:2364”(proximity)	0.570
CASP3	AKT3	psi-mi:“MI:0194”(cleavage reaction)	0.570
AKT3	HSP90AA1	psi-mi:“MI:0914”(association)	0.560
AKT3	HSP90AA1	psi-mi:“MI:0915”(physical association)	0.560
TTC3	AKT3	psi-mi:“MI:0915”(physical association)	0.520
AKT3	TTC3	psi-mi:“MI:0915”(physical association)	0.520
AKT3	PKM	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
CCNA2	AKT3	psi-mi:“MI:0915”(physical association)	0.400
AKT3	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
NUDCD1	AKT3	psi-mi:“MI:0915”(physical association)	0.400
AKT3	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
E	SET	psi-mi:“MI:0914”(association)	0.350
AKT3	COL1A1	psi-mi:“MI:0914”(association)	0.350
AKT3	AKT2	psi-mi:“MI:0914”(association)	0.350
AKT3	NSF	psi-mi:“MI:0914”(association)	0.350
PIANP	TCAF2	psi-mi:“MI:0914”(association)	0.350
KCNE3	PIK3R2	psi-mi:“MI:0914”(association)	0.350
TOX2	TOX4	psi-mi:“MI:0914”(association)	0.350
TSEN2	TMED8	psi-mi:“MI:0914”(association)	0.350
BRAF	AKT3	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	AKT3	psi-mi:“MI:2364”(proximity)	0.270
PRKCZ	AKT3	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (114): PLEKHO1 (Affinity Capture-Western), EIF4EBP1 (Co-fractionation), RPE (Co-fractionation), AKT3 (Co-localization), AKT3 (Co-localization), AKT1 (Affinity Capture-MS), HSP90AB4P (Affinity Capture-MS), HSP90AB3P (Affinity Capture-MS), HSP90AA4P (Affinity Capture-MS), HSP90AA5P (Affinity Capture-MS), AKT3 (Affinity Capture-MS), HSP90AB1 (Affinity Capture-MS), FKBP5 (Affinity Capture-MS), HSP90AA1 (Affinity Capture-MS), CDC37 (Affinity Capture-MS)

ESM2 similar proteins: A2YNT8, A2ZAB5, A9TF79, B6F107, O64812, P0C5D6, P19784, P21869, P31748, P31749, P31750, P31751, P43291, P43292, P47196, P47197, P49137, P49138, P49139, Q01314, Q02066, Q0D4J7, Q16644, Q2QY53, Q39192, Q39193, Q3SYZ2, Q3UMW7, Q5N942, Q60823, Q63484, Q66H84, Q6X4A2, Q6ZI44, Q6ZLP5, Q75H77, Q75LR7, Q75V57, Q7XKA8, Q7XQP4

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

62 interactions.

A	Effect	B	Mechanism
FHIT	down-regulates	AKT3
AKT3	down-regulates	STK3	phosphorylation
PIP3	up-regulates	AKT3	“chemical activation”
MK-2206	down-regulates	AKT3	“chemical inhibition”
AKT3	up-regulates	AGO2	phosphorylation
AKT3	down-regulates	FOXO3	phosphorylation
AKT3	down-regulates	HSPB1	phosphorylation
AKT3	up-regulates	CHUK	phosphorylation
GSK690693	down-regulates	AKT3	“chemical inhibition”
AKT3	down-regulates	STK4	phosphorylation
AKT3	up-regulates	IKK-complex	phosphorylation
AKT3	“up-regulates activity”	TBX3	phosphorylation
PHLPP2	“down-regulates activity”	AKT3	dephosphorylation
AKT3	“up-regulates quantity by stabilization”	POU5F1	phosphorylation
GFs	“up-regulates activity”	AKT3
AKT3	“down-regulates activity”	GSK3B	phosphorylation
PHLPP1	“down-regulates activity”	AKT3	dephosphorylation
PPP2CB	“down-regulates activity”	AKT3	dephosphorylation
PPP2CA	“down-regulates activity”	AKT3	dephosphorylation
PRKCZ	“up-regulates activity”	AKT3	phosphorylation
AKT3	“up-regulates activity”	NOS3	phosphorylation
AKT3	down-regulates	FOXO	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 26 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
Extra-nuclear estrogen signaling	5	44.9×	2e-05
VEGFA-VEGFR2 Pathway	5	36.6×	2e-05
ESR-mediated signaling	5	33.8×	2e-05
Diseases of signal transduction by growth factor receptors and second messengers	5	14.9×	3e-04
Signaling by Receptor Tyrosine Kinases	5	13.6×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to insulin stimulus	5	35.5×	1e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — PROSTATE, SKCM.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	10
Uncertain significance	113
Likely benign	123
Benign	27

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1320062	NM_005465.7(AKT3):c.538A>G (p.Lys180Glu)	Pathogenic
144805	GRCh38/hg38 1q44(chr1:243786629-243870496)x1	Pathogenic
1803517	NM_005465.7(AKT3):c.237G>T (p.Trp79Cys)	Pathogenic
2425356	NC_000001.10:g.(?243652296)(243859038_?)del	Pathogenic
394068	GRCh37/hg19 1q43-44(chr1:243393248-243774475)x1	Pathogenic
39815	NM_005465.7(AKT3):c.686A>G (p.Asn229Ser)	Pathogenic
39816	NM_005465.7(AKT3):c.49G>A (p.Glu17Lys)	Pathogenic
4527055	NM_005465.7(AKT3):c.686A>T (p.Asn229Ile)	Pathogenic
4682499	GRCh37/hg19 1q43-44(chr1:243063909-244418399)x1	Pathogenic
4819641	NM_005465.7(AKT3):c.340G>T (p.Glu114Ter)	Pathogenic
60117	GRCh38/hg38 1q43-44(chr1:237906379-244022201)x1	Pathogenic
814192	GRCh37/hg19 1q43-44(chr1:242709334-244225511)x1	Pathogenic
995385	NM_005465.7(AKT3):c.963T>G (p.Asn321Lys)	Pathogenic
1065925	NM_005465.7(AKT3):c.964G>T (p.Asp322Tyr)	Likely pathogenic
1067297	NC_000001.10:g.(?243652316)(243652442_?)dup	Likely pathogenic
1299320	NM_005465.7(AKT3):c.237G>C (p.Trp79Cys)	Likely pathogenic
1320279	NM_005465.7(AKT3):c.230T>A (p.Leu77His)	Likely pathogenic
273671	NM_005465.7(AKT3):c.548T>A (p.Val183Asp)	Likely pathogenic
426616	NM_005465.7(AKT3):c.481A>C (p.Lys161Gln)	Likely pathogenic
565240	GRCh37/hg19 1q43(chr1:240958055-243698867)x3	Likely pathogenic
635893	Single allele	Likely pathogenic
814194	GRCh37/hg19 1q43-44(chr1:243347610-243871457)x1	Likely pathogenic
974720	NC_000001.11:g.243800225_243853502del	Likely pathogenic

SpliceAI

5098 predictions. Top by Δscore:

Variant	Effect	Δscore
1:243488996:C:CA	acceptor_gain	1.0000
1:243489010:CCAG:C	acceptor_loss	1.0000
1:243489012:A:AG	acceptor_gain	1.0000
1:243489012:A:C	acceptor_loss	1.0000
1:243489013:G:GG	acceptor_gain	1.0000
1:243512318:ACTT:A	donor_loss	1.0000
1:243512320:TTA:T	donor_loss	1.0000
1:243512322:A:AC	donor_gain	1.0000
1:243512322:A:T	donor_loss	1.0000
1:243512323:C:A	donor_loss	1.0000
1:243512323:C:CC	donor_gain	1.0000
1:243512323:CA:C	donor_gain	1.0000
1:243512323:CAT:C	donor_gain	1.0000
1:243512323:CATT:C	donor_gain	1.0000
1:243512323:CATTT:C	donor_gain	1.0000
1:243512422:ACAAG:A	acceptor_gain	1.0000
1:243512423:CAAG:C	acceptor_gain	1.0000
1:243512423:CAAGC:C	acceptor_gain	1.0000
1:243512424:AAG:A	acceptor_gain	1.0000
1:243512424:AAGCT:A	acceptor_loss	1.0000
1:243512425:AG:A	acceptor_gain	1.0000
1:243512426:GCT:G	acceptor_loss	1.0000
1:243512427:C:CC	acceptor_gain	1.0000
1:243512427:CT:C	acceptor_loss	1.0000
1:243512429:G:C	acceptor_gain	1.0000
1:243512429:G:GC	acceptor_gain	1.0000
1:243545504:TCTTA:T	donor_loss	1.0000
1:243545505:CTTA:C	donor_loss	1.0000
1:243545506:TTA:T	donor_loss	1.0000
1:243545507:TACC:T	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000000477 (1:243600298 A>G), RS1000014692 (1:243610862 T>C), RS1000017470 (1:243617295 T>C), RS1000025845 (1:243493328 TG>T,TGG), RS1000031160 (1:243736167 A>G), RS1000033459 (1:243808364 C>G,T), RS1000034343 (1:243642303 T>C), RS1000041676 (1:243589335 G>A,C,T), RS1000058438 (1:243656154 C>T), RS1000081017 (1:243600512 T>C), RS1000085387 (1:243808067 C>T), RS1000097980 (1:243738053 C>T), RS1000101829 (1:243517811 G>A,T), RS1000104075 (1:243557783 T>C), RS1000116057 (1:243790649 G>A)

Disease associations

OMIM: gene MIM:611223 | disease phenotypes: MIM:613615, MIM:615993, MIM:615937, MIM:602501

GenCC curated gene-disease

Disease	Classification	Inheritance
overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	Definitive	Autosomal dominant
megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2	Strong	Autosomal dominant
megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1	Strong	Autosomal dominant
megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome	Supportive	Autosomal dominant
microcephaly	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	Definitive	AD
microcephaly	Limited	AD

Mondo (13): Senior-Loken syndrome 7 (MONDO:0013326), Bardet-Biedl syndrome 16 (MONDO:0014444), megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (MONDO:0014407), overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes (MONDO:0100283), polymicrogyria (MONDO:0000087), capillary hemangioma (MONDO:0002407), megalencephaly-capillary malformation-polymicrogyria syndrome (MONDO:0011240), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092), megacolon (MONDO:0001273), microcephaly (MONDO:0001149), megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome (MONDO:0019375), megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (MONDO:0011313)

Orphanet (6): Bardet-Biedl syndrome (Orphanet:110), Senior-Loken syndrome (Orphanet:3156), Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome (Orphanet:83473), Polymicrogyria (Orphanet:35981), Megalencephaly-capillary malformation-polymicrogyria syndrome (Orphanet:60040), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000160	Narrow mouth
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000267	Cranial asymmetry
HP:0000316	Hypertelorism
HP:0000348	High forehead
HP:0000506	Telecanthus
HP:0000648	Optic atrophy
HP:0000929	Abnormal skull morphology
HP:0000965	Cutis marmorata
HP:0000974	Hyperextensible skin
HP:0001162	Postaxial hand polydactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001269	Hemiparesis
HP:0001302	Pachygyria
HP:0001336	Myoclonus
HP:0001355	Megalencephaly
HP:0001629	Ventricular septal defect
HP:0001653	Mitral regurgitation
HP:0001671	Abnormal cardiac septum morphology
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002126	Polymicrogyria
HP:0002133	Status epilepticus
HP:0002171	Gliosis
HP:0002282	Gray matter heterotopia
HP:0002392	EEG with polyspike wave complexes

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST000451_16	RR interval (heart rate)	2.000000e-06
GCST001017_13	Diabetic retinopathy	2.000000e-06
GCST001017_8	Diabetic retinopathy	1.000000e-07
GCST001973_15	Menarche (age at onset)	5.000000e-06
GCST001973_3	Menarche (age at onset)	1.000000e-07
GCST002037_13	Post-traumatic stress disorder (asjusted for relatedness)	6.000000e-06
GCST002149_19	Schizophrenia	2.000000e-08
GCST002539_35	Schizophrenia	4.000000e-09
GCST002598_65	Educational attainment	2.000000e-06
GCST004348_14	Non-glioblastoma glioma	3.000000e-10
GCST004946_107	Schizophrenia	7.000000e-10
GCST006190_23	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	4.000000e-16
GCST006190_30	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	3.000000e-20
GCST006193_14	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	2.000000e-20
GCST006193_54	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	4.000000e-17
GCST006461_20	Self-reported risk-taking behaviour	3.000000e-10
GCST006803_108	Schizophrenia	2.000000e-10
GCST007201_134	Schizophrenia	2.000000e-10
GCST007201_296	Schizophrenia	2.000000e-07
GCST007201_401	Schizophrenia	4.000000e-07
GCST007324_73	Adventurousness	9.000000e-14
GCST008163_156	Height	6.000000e-08
GCST009312_15	Antisaccade task score	3.000000e-06
GCST010241_291	Apolipoprotein A1 levels	7.000000e-09
GCST010697_26	Cortical surface area (min-P)	2.000000e-08
GCST010698_11	Subcortical volume (min-P)	5.000000e-09
GCST010699_68	Brain morphology (min-P)	8.000000e-20
GCST010700_14	Cortical thickness (MOSTest)	9.000000e-13
GCST010701_125	Cortical surface area (MOSTest)	9.000000e-11
GCST010702_14	Subcortical volume (MOSTest)	5.000000e-08

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004831	RR interval
EFO:0004703	age at menarche
EFO:0004784	self reported educational attainment
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0008579	risk-taking behaviour
EFO:0007969	cognitive inhibition measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0600001	ghrelin measurement
EFO:0005091	monocyte count
EFO:0007984	platelet component distribution width

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D018324	Hemangioma, Capillary	C04.557.645.375.380
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008531	Megacolon	C06.405.469.158.701
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
D065706	Polymicrogyria	C10.500.507.500.500; C16.131.666.507.500.500
C566381	Megalancephaly Polymicrogyria-Polydactyly Hydrocephalus Syndrome (supp.)
C536142	Megalencephaly cutis marmorata telangiectatica congenita (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL2111353 (PROTEIN FAMILY), CHEMBL4816 (SINGLE PROTEIN), CHEMBL5291687 (PROTEIN-PROTEIN INTERACTION), CHEMBL6177912 (PROTEIN-PROTEIN INTERACTION), CHEMBL6177913 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

18 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 38,025 (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
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL2177390	IPATASERTIB	3	2,231
CHEMBL2219422	AFURESERTIB	3	1,467
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL38380	FASUDIL	3	11,953
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL4297188	MIRANSERTIB	2	769
CHEMBL1079175	MK-2206	2	3,008
CHEMBL3137336	UPROSERTIB	2	1,624
CHEMBL3544960	AT-13148	1	779
CHEMBL494089	GSK-690693	1	2,061
CHEMBL1090479	GSK-1070916	1	177
CHEMBL3109738	JNJ-26483327	1	862
CHEMBL3128043	PF-03758309	1	233
CHEMBL4751394	BAY-1125976	1	89
CHEMBL4802156	VEVORISERTIB	1	70

Clinical evidence (CIViC)

Drug × variant × indication: 5 predictive associations from 5 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
AKT3 E17K	Vemurafenib	Melanoma	Resistance	CIViC D	EID4521
AKT3 Overexpression	Akt Inhibitor MK2206	Breast Cancer	Resistance	CIViC D	EID1922
AKT3 Overexpression	Pan-AKT Kinase Inhibitor GSK690693	Breast Cancer	Resistance	CIViC D	EID3001
AKT3 Overexpression	Vemurafenib	Melanoma	Resistance	CIViC D	EID6261
AKT3 Overexpression	Pan-AKT Kinase Inhibitor GSK690693	Triple-receptor Negative Breast Cancer	Sensitivity/Response	CIViC E	EID1923

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

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 (16 total), top 16:

Ligand	Action	Affinity	Parameter
NTQ1062	Inhibition	10.0	pIC50
rizavasertib	Inhibition	9.8	pKi
rupitasertib	Inhibition	9.0	pIC50
compound 1 [PMID: 20005102]	Inhibition	9.0	pIC50
uprosertib	Inhibition	8.82	pKi
compound E22 [PMID: 31298542]	Inhibition	8.77	pIC50
afuresertib	Inhibition	8.59	pKi
capivasertib	Inhibition	8.1	pIC50
ipatasertib	Inhibition	8.1	pIC50
GSK690693	Inhibition	8.05	pIC50
miransertib	Inhibition	7.8	pIC50
pifusertib	Inhibition	7.36	pIC50
MK-2206	Negative	7.19	pIC50
MS15	Inhibition	6.26	pIC50
Akt inhibitor VIII	Negative	5.67	pIC50
engasertib	Inhibition	5.56	pIC50

Binding affinities (BindingDB)

62 measured of 70 human assays (70 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-(3-{[2-(4-methoxyphenyl)ethyl]amino}propoxy)-1H-imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	IC50	5 nM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-7-(4-aminobutoxy)-1-ethyl-1H-imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	IC50	9 nM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-(piperidin-4-ylmethoxy)-1H-imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	IC50	10 nM
(2R)-6-amino-2-(6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}hexanamido)-N-(5-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}pentyl)hexanamide	IC50	14.6 nM
1-[1-({4-[3-phenyl-7-(2H-1,2,3,4-tetrazol-5-yl)quinoxalin-2-yl]phenyl}methyl)piperidin-4-yl]-2,3-dihydro-1H-1,3-benzodiazol-2-one	IC50	20 nM
N-[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}butyl]-6-{[2-(isoquinoline-5-sulfonamido)ethyl]amino}hexanamide	IC50	30.7 nM
6-{5-[(2S)-2-amino-3-(1H-indol-3-yl)propoxy]pyridin-3-yl}isoquinolin-3-amine	IC50	31 nM
6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}-N-[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}butyl]hexanamide	IC50	36.9 nM
6-{[(1S,3R,4R)-3-(6-amino-9H-purin-9-yl)-4-hydroxycyclopentyl]formamido}-N-[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}butyl]hexanamide	IC50	43.1 nM
1-[1-({4-[7-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)-3-phenylquinoxalin-2-yl]phenyl}methyl)piperidin-4-yl]-2,3-dihydro-1H-1,3-benzodiazol-2-one	IC50	55 nM
4-[1-ethyl-7-(piperidin-4-ylmethoxy)-1H-imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine	IC50	56 nM
(2R)-6-amino-2-(6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}hexanamido)-N-(5-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}pentyl)hexanamide	IC50	56.6 nM
1-[1-({4-[3-phenyl-6-(2H-1,2,3,4-tetrazol-5-yl)quinoxalin-2-yl]phenyl}methyl)piperidin-4-yl]-2,3-dihydro-1H-1,3-benzodiazol-2-one	IC50	63 nM
4-[1-ethyl-7-(piperidin-4-yloxy)-1H-imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine	IC50	79 nM
pyrazoloquinoxaline	IC50	85 nM
2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-N-[2-(methylamino)ethyl]-1H-imidazo[4,5-c]pyridine-7-carboxamide	IC50	126 nM
3-(4-{[4-(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidin-1-yl]methyl}phenyl)-2-phenylquinoxaline-6-carboxylic acid	IC50	166 nM
({4-[3-phenyl-5-(1H-1,2,3,4-tetrazol-5-yl)pyridin-2-yl]phenyl}methyl)({[4-(1,2,3-thiadiazol-4-yl)phenyl]methyl})amine	IC50	177 nM
4-{1-ethyl-7-[(piperidin-4-ylamino)methyl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,2,5-oxadiazol-3-amine	IC50	200 nM
9-[1-({4-[3-phenyl-5-(1H-1,2,3,4-tetrazol-5-yl)pyridin-2-yl]phenyl}methyl)piperidin-4-yl]-9H-purin-6-amine	IC50	210 nM
6-fluoro-2-[1-({4-[3-phenyl-5-(1H-1,2,3,4-tetrazol-5-yl)pyridin-2-yl]phenyl}methyl)piperidin-4-yl]-1H-1,3-benzodiazole	IC50	239 nM
2-(4-{[4-(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidin-1-yl]methyl}phenyl)-3-phenylquinoxaline-6-carboxylic acid	IC50	240 nM
6-{5-[(2S)-2-amino-3-(1H-indol-3-yl)propoxy]-2-ethynylpyridin-3-yl}isoquinoline	IC50	260 nM
13a (S-)	IC50	270 nM
1-[1-({4-[3-phenyl-5-(1H-1,2,3,4-tetrazol-5-yl)pyridin-2-yl]phenyl}methyl)piperidin-4-yl]-2,3-dihydro-1H-1,3-benzodiazol-2-one	IC50	273 nM
1-(1-{[4-(3-phenylquinoxalin-2-yl)phenyl]methyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one	IC50	290 nM
4-(7-{[(3R)-3-aminopyrrolidin-1-yl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine	IC50	331 nM
1-(1-{[4-(3-phenylquinolin-2-yl)phenyl]methyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one	IC50	365 nM
4-[1-ethyl-7-(piperazin-1-ylcarbonyl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine	IC50	501 nM
6-{5-[(2S)-2-amino-3-(1H-indol-3-yl)propoxy]-2-chloropyridin-3-yl}isoquinoline	IC50	540 nM
2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-N-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridine-7-carboxamide	IC50	562 nM
2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-N-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridine-7-carboxamide	IC50	631 nM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1^{7,14}.0^{2,6}.0^{8,13}.0^{22,27}]nonacosa-1(28),2(6),7(29),8(13),9,11,22(27),23,25-nonaene-3,5-dione	KD	700 nM
1-(1-{[4-(6-methyl-5-oxo-3-phenyl-4,5-dihydropyrazin-2-yl)phenyl]methyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one	IC50	760 nM
6-(4-{[4-(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylpyridine-3-carbonitrile	IC50	762 nM
6-methyl-2-[1-({4-[3-phenyl-5-(1H-1,2,3,4-tetrazol-5-yl)pyridin-2-yl]phenyl}methyl)piperidin-4-yl]-1H-1,3-benzodiazole	IC50	763 nM
(2R)-6-amino-2-(6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}hexanamido)-N-(5-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}butyl]carbamoyl}pentyl)hexanamide	IC50	774 nM
6-(4-{[4-(6-fluoro-1H-1,3-benzodiazol-2-yl)piperidin-1-yl]methyl}phenyl)-5-phenylpyridine-3-carbonitrile	IC50	865 nM
1-(1-{[4-(5-methyl-6-oxo-3-phenyl-1,6-dihydropyrazin-2-yl)phenyl]methyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one	IC50	1000 nM
1-[1-({4-[6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)-3-phenylquinoxalin-2-yl]phenyl}methyl)piperidin-4-yl]-2,3-dihydro-1H-1,3-benzodiazol-2-one	IC50	1090 nM
3-[(2S)-2-amino-3-({5-[(E)-2-(pyridin-4-yl)ethenyl]pyridin-3-yl}oxy)propyl]-1H-indole	IC50	1200 nM
5-phenyl-6-{4-[({[4-(1,2,3-thiadiazol-4-yl)phenyl]methyl}amino)methyl]phenyl}pyridine-3-carbonitrile	IC50	1290 nM
6-(4-{[4-(1H-1,3-benzodiazol-2-yl)piperidin-1-yl]methyl}phenyl)-5-phenylpyridine-3-carbonitrile	IC50	1470 nM
1-(1-{[4-(6-oxo-3-phenyl-1,6-dihydropyrazin-2-yl)phenyl]methyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one	IC50	1500 nM
6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}-N-[(1R)-4-carbamimidamido-1-carbamoylbutyl]hexanamide	IC50	1610 nM
6-{[(1S,3R,4R)-3-(6-amino-9H-purin-9-yl)-4-hydroxycyclopentyl]formamido}-N-[(1R)-1-[(5-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}butyl]carbamoyl}pentyl)carbamoyl]ethyl]hexanamide	IC50	2040 nM
6-(4-{[4-(6-methyl-1H-1,3-benzodiazol-2-yl)piperidin-1-yl]methyl}phenyl)-5-phenylpyridine-3-carbonitrile	IC50	2870 nM
1-(1-{[4-(5-oxo-3-phenyl-4,5-dihydropyrazin-2-yl)phenyl]methyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one	IC50	3030 nM
1-(1-{[4-(2-phenylquinolin-3-yl)phenyl]methyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one	IC50	3140 nM

ChEMBL bioactivities

664 potent at pChembl≥5 of 696 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL4457064
10.00	IC50	0.1	nM	CHEMBL5169427
10.00	IC50	0.1	nM	CHEMBL5197007
10.00	IC50	0.1	nM	CHEMBL5182446
9.92	IC50	0.12	nM	CHEMBL4441825
9.70	IC50	0.2	nM	Borussertib
9.70	IC50	0.2	nM	CHEMBL5175332
9.70	IC50	0.2	nM	CHEMBL5195745
9.70	IC50	0.2	nM	CHEMBL5175628
9.70	IC50	0.2	nM	CHEMBL5180219
9.70	IC50	0.2	nM	CHEMBL5190230
9.52	IC50	0.3	nM	CHEMBL5206905
9.52	IC50	0.3	nM	CHEMBL5177491
9.52	IC50	0.3	nM	CHEMBL5426352
9.40	IC50	0.4	nM	CHEMBL5195664
9.40	IC50	0.4	nM	CHEMBL5189707
9.30	IC50	0.5	nM	CHEMBL5187172
9.30	IC50	0.5	nM	CHEMBL5171561
9.30	IC50	0.5	nM	CHEMBL5193325
9.19	IC50	0.64	nM	STAUROSPORINE
9.15	IC50	0.7	nM	CHEMBL5187508
9.05	IC50	0.9	nM	CHEMBL5414256
9.00	IC50	1	nM	CHEMBL2177387
9.00	IC50	1	nM	CHEMBL3919089
9.00	IC50	1	nM	CHEMBL482536
9.00	IC50	1	nM	CHEMBL5189610
9.00	IC50	1	nM	CHEMBL5406950
9.00	IC50	1	nM	CHEMBL5402470
9.00	IC50	1	nM	CHEMBL593374
9.00	IC50	1	nM	CHEMBL605410
9.00	IC50	1	nM	CHEMBL594072
9.00	IC50	1	nM	CHEMBL593490
9.00	IC50	1	nM	CHEMBL594933
9.00	IC50	1	nM	CHEMBL1099276
8.92	IC50	1.2	nM	CHEMBL5192188
8.92	IC50	1.2	nM	CHEMBL5199199
8.89	IC50	1.3	nM	UPROSERTIB
8.89	IC50	1.3	nM	VEVORISERTIB
8.87	IC50	1.34	nM	CHEMBL4792262
8.85	IC50	1.4	nM	CHEMBL4853207
8.82	IC50	1.5	nM	UPROSERTIB
8.80	IC50	1.585	nM	AFURESERTIB
8.80	IC50	1.6	nM	CHEMBL5187287
8.77	IC50	1.7	nM	CHEMBL4440965
8.70	IC50	2	nM	CHEMBL2177361
8.70	IC50	2	nM	CHEMBL2178598
8.70	IC50	2	nM	CHEMBL470597
8.70	IC50	2	nM	CHEMBL524998
8.70	IC50	2	nM	CHEMBL523586
8.70	IC50	2	nM	CHEMBL496690

PubChem BioAssay actives

542 with measured affinity, of 2742 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
(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	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0001	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	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0001	uM
5-chloro-4-(4-chloro-1-methylpyrazol-5-yl)-N-[(3S,4S,6S)-4-(3,4-difluorophenyl)-6-(2-hydroxyethyl)piperidin-3-yl]furan-2-carboxamide	1608040: Inhibition of Akt3 (unknown origin) by mobile shift assay	ic50	0.0001	uM
5-chloro-4-(4-chloro-1-methylpyrazol-5-yl)-N-[(3S,4S)-4-(3,4-difluorophenyl)piperidin-3-yl]furan-2-carboxamide;(2R,3R)-2,3-dihydroxybutanedioic acid	1608040: Inhibition of Akt3 (unknown origin) by mobile shift assay	ic50	0.0001	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	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0001	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	1866987: Inhibition of AKT (unknown origin)	ic50	0.0002	uM
(4S)-5-[4-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]piperazin-1-yl]-4-methyl-1,4-dihydropyrimido[4,5-d][1,3]oxazin-2-one	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0002	uM
(5R)-4-[8-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0002	uM
4-[8-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-5-methyl-6,8-dihydropteridin-7-one;formic acid	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0002	uM
(4S)-5-[(1R,5S)-3-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-methyl-1,4-dihydropyrimido[4,5-d][1,3]oxazin-2-one	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0002	uM
(5R)-4-[4-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-2,2,3,3,5,5,6,6-octadeuteriopiperazin-1-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0002	uM
(5R)-4-[4-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]piperazin-1-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0003	uM
(5R)-4-[3-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0003	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
4-[4-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]piperazin-1-yl]-5-methyl-6,8-dihydropteridin-7-one;hydrochloride	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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
(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	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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-[(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-dihydropteridin-7-one	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0005	uM
4-[(1R,5S)-3-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-methyl-6,8-dihydropteridin-7-one	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0005	uM
(5R)-4-[(1S,6R)-5-[(2S)-2-(4-chlorophenyl)-3-[(4-methoxycyclohexyl)amino]propanoyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0005	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	415638: Inhibition of AKT3	ic50	0.0006	uM
(5R)-4-[(1S,6R)-5-[(2S)-3-amino-2-(4-chlorophenyl)propanoyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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
2-[[(1R)-1-(3-cyano-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	0.0009	uM
6-[4-[1-[2-(azetidin-1-yl)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidin-1-yl]-5-chloropyrimidin-4-amine	1766232: Inhibition of Akt (unknown origin)	ic50	0.0010	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	477362: Inhibition of AKT3	ic50	0.0010	uM
(5R)-4-[4-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]piperazin-1-yl]-5-(trifluoromethyl)-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0010	uM
2-[[(1R)-1-[3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxopyrido[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	0.0010	uM
2-[[(1R)-1-[3-cyano-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-oxopyrido[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	0.0010	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	417621: Inhibition of AKT3	ic50	0.0010	uM
(2S)-1-[[6-(furan-3-yl)-5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-(1H-indol-3-yl)propan-2-amine	454233: Inhibition of AKT3	ic50	0.0010	uM
(2S)-1-[[6-(furan-3-yl)-5-(3-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-3-pyridinyl]oxy]-3-(1H-indol-3-yl)propan-2-amine	454233: Inhibition of AKT3	ic50	0.0010	uM
3-[(2S)-2-amino-3-(1H-indol-3-yl)propoxy]-6-(2-methylfuran-3-yl)-5-(3-methyl-2H-indazol-5-yl)pyridin-2-amine	455026: Inhibition of human AKT3	ic50	0.0010	uM
3-[(2S)-2-amino-3-[[2-amino-6-(2-methylfuran-3-yl)-5-(3-methyl-2H-pyrazolo[3,4-b]pyrazin-5-yl)-3-pyridinyl]oxy]propyl]-1H-indole-2-carbonitrile	455026: Inhibition of human AKT3	ic50	0.0010	uM
3-[(2S)-2-amino-3-[[2-amino-6-(2-methylfuran-3-yl)-5-(3-methyl-2H-pyrazolo[3,4-b]pyrazin-5-yl)-3-pyridinyl]oxy]propyl]-1H-indole-2-carboxamide	455026: Inhibition of human AKT3	ic50	0.0010	uM
(2S)-2-(4-chlorophenyl)-1-[4-[(5S)-5-ethenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]piperazin-1-yl]-3-(propan-2-ylamino)propan-1-one	708171: Competitive inhibition of wild-type full-length amino-terminal polyhistidine-tagged human Akt3 expressed in recombinant baculovirus system using fluorescence labeled Crosstide as substrate after 60 mins by fluorescence polarization assay in presence of ATP	ic50	0.0010	uM
5-[4-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]piperazin-1-yl]-4-methyl-1,4-dihydropyrimido[4,5-d][1,3]oxazin-2-one	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0012	uM
(5R)-4-[(1S,6R)-5-[(2S)-2-(4-chlorophenyl)-3-(3-oxabicyclo[3.1.0]hexan-6-ylamino)propanoyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0012	uM
2-iodo-N-[2-(4-nitroanilino)-2-oxo-1-phenylethyl]-N-phenylbenzamide	1687404: Inhibition of human AKT assessed as inhibition of substrate phosphorylation using AKTide-2T as substrate	ic50	0.0013	uM
N-[(2S)-1-amino-3-(3,4-difluorophenyl)propan-2-yl]-5-chloro-4-(4-chloro-1-methylpyrazol-5-yl)furan-2-carboxamide	1608040: Inhibition of Akt3 (unknown origin) by mobile shift assay	ic50	0.0013	uM
N-[1-[3-[3-[4-(1-aminocyclobutyl)phenyl]-2-(2-amino-3-pyridinyl)imidazo[4,5-b]pyridin-5-yl]phenyl]piperidin-4-yl]-N-methylacetamide	1922445: Inhibition of AKT3 (unknown origin)	ic50	0.0013	uM
4-[[(1S)-2-(azetidin-1-yl)-1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl]amino]quinazoline-8-carboxylic acid	1766232: Inhibition of Akt (unknown origin)	ic50	0.0014	uM
4-[4-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]piperazin-1-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one	1912111: Inhibition of recombinant N-terminal GST tagged AKT2 (108 to 479 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	0.0016	uM
5-chloro-4-(4-chloro-1-methylpyrazol-5-yl)-N-[(3S,4S,6S)-4-(3,4-difluorophenyl)-6-[2-(methylamino)-2-oxoethyl]piperidin-3-yl]furan-2-carboxamide	1608040: Inhibition of Akt3 (unknown origin) by mobile shift assay	ic50	0.0017	uM
2-[[(1R)-1-[3-cyano-2-(3,3-difluoroazetidin-1-yl)-7-methyl-4-oxopyrido[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	0.0020	uM
N-[(2S)-1-amino-3-phenylpropan-2-yl]-4-bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiophene-2-carboxamide	417621: Inhibition of AKT3	ic50	0.0020	uM
3-[(2S)-2-amino-3-(1H-indol-3-yl)propoxy]-6-(2-methylfuran-3-yl)-5-(3-methyl-2H-pyrazolo[3,4-b]pyrazin-5-yl)pyridin-2-amine	455026: Inhibition of human AKT3	ic50	0.0020	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	417621: Inhibition of AKT3	ic50	0.0020	uM
N-[(2S)-1-amino-3-(4-methoxyphenyl)propan-2-yl]-4-bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiophene-2-carboxamide	417621: Inhibition of AKT3	ic50	0.0020	uM
N-[(2S)-1-amino-3-(2-fluorophenyl)propan-2-yl]-4-bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiophene-2-carboxamide	417621: Inhibition of AKT3	ic50	0.0020	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	417621: Inhibition of AKT3	ic50	0.0020	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	417621: Inhibition of AKT3	ic50	0.0020	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, affects splicing, affects cotreatment, increases abundance (+1 more)	5
Cadmium Chloride	increases expression, increases reaction, decreases reaction, increases abundance, increases phosphorylation (+1 more)	5
bisphenol A	decreases expression, decreases phosphorylation, increases phosphorylation, affects cotreatment, increases methylation	4
methylmercuric chloride	increases expression, affects cotreatment, decreases expression	3
trichostatin A	affects cotreatment, decreases expression	3
Particulate Matter	increases abundance, increases expression, decreases expression, affects expression, decreases methylation	3
arsenite	affects expression, decreases expression	2
cobaltous chloride	decreases expression, affects cotreatment, decreases phosphorylation	2
potassium chromate(VI)	affects cotreatment, decreases expression	2
epigallocatechin gallate	decreases phosphorylation, decreases reaction, affects cotreatment, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Resveratrol	affects cotreatment, decreases phosphorylation, decreases expression	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Curcumin	decreases phosphorylation, decreases reaction, increases phosphorylation, decreases expression, affects reaction	2
Valproic Acid	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
GSK2110183	decreases activity	1
GSK2141795	decreases activity	1
FR900359	increases phosphorylation	1
peracetylated N-azidoacetylmannosamine	decreases expression	1
pralsetinib	affects cotreatment, decreases phosphorylation	1
sotorasib	affects cotreatment, decreases expression	1
geldanamycin	increases expression	1
beta-N-methylamino-L-alanine	decreases expression	1
oxybenzone	increases expression	1
triphenyl phosphate	affects expression	1
nuciferine	decreases reaction, affects cotreatment, decreases phosphorylation	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects expression	1

ChEMBL screening assays

660 unique, capped per target: 644 binding, 16 functional

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

Cellosaurus cell lines

11 cell lines: 10 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A2PQ	DLD-1 AKT3(-/-)	Cancer cell line	Male
CVCL_B1JE	Abcam HeLa AKT3 KO	Cancer cell line	Female
CVCL_B5N7	MFUM-BrTNBC-1	Cancer cell line	Female
CVCL_B8B7	Abcam HCT 116 AKT3 KO	Cancer cell line	Male
CVCL_B8SB	Abcam MCF-7 AKT3 KO	Cancer cell line	Female
CVCL_B9D9	Abcam A-549 AKT3 KO	Cancer cell line	Male
CVCL_D7JZ	Ubigene A-549 AKT3 KO	Cancer cell line	Male
CVCL_D8Z0	Ubigene HEK293 AKT3 KO	Transformed cell line	Female
CVCL_DH75	D40	Cancer cell line	Sex unspecified
CVCL_SC15	HAP1 AKT3 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04288700	PHASE4	UNKNOWN	Evaluation of the Efficacy of Captopril Versus Propranolol and Timolol as a Treatment of Infantile Capillary Hemangioma
NCT05479123	PHASE4	TERMINATED	Assessing the Impact of Dosage Frequency of Propranolol on Sleep Patterns in Patients With Infantile Hemangiomas
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02505971	PHASE3	COMPLETED	Nadolol Versus Propranolol in Children With Infantile Hemangiomas
NCT03237637	PHASE3	UNKNOWN	Comparative Study to Evaluate the Effectiveness of Atenolol and Propranolol in the Treatment of Infantile Hemangiomas
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT01010308	PHASE2	COMPLETED	Nadolol for Proliferating Infantile Hemangiomas
NCT01408056	PHASE2	WITHDRAWN	Timolol Option for Ulcerated Hemangiomas (TOUCH Trial)
NCT01512173	PHASE2	COMPLETED	Study in Infants With Infantile Hemangioma to Compare Propranolol Gel to Placebo
NCT02913612	PHASE2	COMPLETED	Efficacy, Safety and Pharmacokinetics of Topical Timolol in Infants With Infantile Hemangioma (IH)
NCT04684667	PHASE2	UNKNOWN	‘‘Efficacy of Propranolol in the Treatment of Infantile Hemangioma
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT01434849	PHASE1	TERMINATED	Timolol for the Prevention of Proliferation of Infantile Hemangioma (TiPPIH Trial)
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors