PIK3R1

Summary

PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1, HGNC:8979) is a protein-coding gene on chromosome 5q13.1, encoding Phosphatidylinositol 3-kinase regulatory subunit alpha (P27986). Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. In precision oncology, PIK3CA Mutation OR PTEN Mutation OR PIK3R1 Mutation confers sensitivity to Aspirin in Colorectal Cancer (CIViC Level B); 2 further curated variant–drug associations are listed below.

Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. The enzyme comprises a 110 kD catalytic subunit and a regulatory subunit of either 85, 55, or 50 kD. This gene encodes the 85 kD regulatory subunit. Phosphatidylinositol 3-kinase plays an important role in the metabolic actions of insulin, and a mutation in this gene has been associated with insulin resistance. Alternative splicing of this gene results in four transcript variants encoding different isoforms.

Source: NCBI Gene 5295 — RefSeq curated summary.

At a glance

• Gene–disease (curated): PIK3R1-related immunodeficiency and SHORT syndrome (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 37
• Clinical variants (ClinVar): 753 total — 43 pathogenic, 31 likely-pathogenic
• Phenotypes (HPO): 144
• Druggable target: yes — 26 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 3 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 15 cancer types
• MANE Select transcript: NM_181523

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8979
Approved symbol	PIK3R1
Name	phosphoinositide-3-kinase regulatory subunit 1
Location	5q13.1
Locus type	gene with protein product
Status	Approved
Aliases	GRB1, p85-ALPHA, p85, p85alpha
Ensembl gene	ENSG00000145675
Ensembl biotype	protein_coding
OMIM	171833
Entrez	5295

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 31 protein_coding, 5 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000320694, ENST00000336483, ENST00000517412, ENST00000517643, ENST00000517698, ENST00000518292, ENST00000518813, ENST00000519025, ENST00000520550, ENST00000520675, ENST00000521381, ENST00000521409, ENST00000521657, ENST00000522084, ENST00000523807, ENST00000523872, ENST00000697457, ENST00000697458, ENST00000697459, ENST00000697460, ENST00000697461, ENST00000697462, ENST00000697463, ENST00000697464, ENST00000697465, ENST00000697466, ENST00000697467, ENST00000697468, ENST00000697469, ENST00000697470, ENST00000697555, ENST00000697556, ENST00000697557, ENST00000870049, ENST00000870050, ENST00000870051, ENST00000870052, ENST00000870053, ENST00000961622, ENST00000961623

RefSeq mRNA: 4 — MANE Select: NM_181523 NM_001242466, NM_181504, NM_181523, NM_181524

CCDS: CCDS3993, CCDS3994, CCDS3995, CCDS56374

Canonical transcript exons

ENST00000521381 — 16 exons

Exon	Start	End
ENSE00000971572	68279602	68279733
ENSE00000971574	68280927	68281006
ENSE00001810153	68297412	68301821
ENSE00002136147	68215756	68215949
ENSE00003497036	68293303	68293483
ENSE00003524335	68292259	68292361
ENSE00003536262	68295420	68295488
ENSE00003592058	68294536	68294678
ENSE00003597128	68295148	68295324
ENSE00003607581	68280528	68280729
ENSE00003648923	68296171	68296341
ENSE00003664046	68293709	68293834
ENSE00003785806	68293101	68293199
ENSE00003970714	68273939	68274013
ENSE00003970930	68273390	68273482
ENSE00003970937	68226290	68227009

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 65.4730 / max 5325.1909, expressed in 1786 samples.

FANTOM5 promoters (21 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56795	47.2937	1782
56813	6.9477	393
56803	2.6671	127
56802	2.4947	122
56810	1.0949	429
56814	0.7758	128
56805	0.6561	99
56809	0.5926	234
56796	0.5600	249
56797	0.4081	145

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.71	gold quality
caput epididymis	UBERON:0004358	99.18	gold quality
corpus epididymis	UBERON:0004359	99.15	gold quality
postcentral gyrus	UBERON:0002581	99.11	gold quality
mammary duct	UBERON:0001765	99.09	gold quality
parietal lobe	UBERON:0001872	99.07	gold quality
epithelium of mammary gland	UBERON:0003244	98.85	gold quality
cauda epididymis	UBERON:0004360	98.84	gold quality
trigeminal ganglion	UBERON:0001675	98.78	gold quality
middle temporal gyrus	UBERON:0002771	98.73	gold quality
superior frontal gyrus	UBERON:0002661	98.59	gold quality
lateral globus pallidus	UBERON:0002476	98.41	gold quality
pericardium	UBERON:0002407	98.25	gold quality
entorhinal cortex	UBERON:0002728	98.02	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.00	gold quality
nipple	UBERON:0002030	97.88	gold quality
globus pallidus	UBERON:0001875	97.80	gold quality
endothelial cell	CL:0000115	97.73	gold quality
inferior vagus X ganglion	UBERON:0005363	97.67	gold quality
lower lobe of lung	UBERON:0008949	97.63	gold quality
decidua	UBERON:0002450	97.61	gold quality
medial globus pallidus	UBERON:0002477	97.61	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.61	gold quality
mammary gland	UBERON:0001911	97.60	gold quality
thoracic mammary gland	UBERON:0005200	97.60	gold quality
orbitofrontal cortex	UBERON:0004167	97.59	gold quality
endometrium	UBERON:0001295	97.54	gold quality
dorsal root ganglion	UBERON:0000044	97.46	gold quality
occipital lobe	UBERON:0002021	97.42	gold quality
corpus callosum	UBERON:0002336	97.31	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-CURD-89	yes	2026.87
E-HCAD-6	yes	231.51
E-HCAD-4	yes	120.96
E-CURD-122	yes	46.08
E-CURD-88	yes	41.56
E-CURD-46	yes	29.93
E-GEOD-135922	yes	24.25
E-HCAD-10	yes	23.80
E-CURD-119	yes	14.36
E-GEOD-125970	yes	13.45
E-MTAB-7606	no	564.90
E-MTAB-10553	no	11.13
E-MTAB-9543	no	2.36
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, BHLHE40, CUX1, E2F3, EGR1, EPAS1, ESR1, ETS2, FOXO3, HIF1A, HMGA1, ID1, IRF6, ITGAX, JUN, KLF8, LITAF, MDM2, MEF2A, MITF, MNX1, MTA1, MYC, MYOD1, NFATC4, NFE2L2, NFKB, NR0B1, NRG1, REST, SP1, SREBF1, SSRP1, STAT1, STAT3, STAT4, STAT5A, TP53, TXK

miRNA regulators (miRDB)

241 targeting PIK3R1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939

Literature-anchored findings (GeneRIF, showing 40)

• The winged-helix transcription factor JUMU is a haplo-suppressor/triplo-enhancer of PEV in various tissues but exhibits reverse PEV effects in the brain of Drosophila melanogaster. (PMID:19301136)
• Mutations of the PEV-modifying jumu gene result in an extreme nucleolus disorganization. (PMID:20213139)
• Both jumu and CHES-1-like are required during asymmetric cell division for the derivation of two distinct cardiac cell types from their mutual precursor and in symmetric cell divisions that produce yet a third type of heart cell. (PMID:22814603)
• The results suggest a Jumu-mediated crosstalk between hematopoiesis and the fat body, especially during the Toll-dependent formation of melanotic nodules. (PMID:27507244)
• Jumeau (Jumu), a member of the forkhead (Fkh) transcription factor family, controls hemocyte differentiation of lymph gland through multiple regulatory mechanisms. (PMID:28350299)
• Jumu is required for circulating hemocyte differentiation and phagocytosis in Drosophila (PMID:30518379)
• Loss of Jumeau (Jumu) function triggers apoptosis via a JNK-dependent pathway in wing development. jumu mutants show reduced wing size, a loss of the anterior cross vein (ACV) phenotype, and increased apoptosis. The JNK signaling markers puckered (puc) and p-JNK are increased in the wing discs of jumu mutants. Apoptosis induced by the loss of jumu is rescued by knocking down JNK. (PMID:30796611)
• Study reports that Drosophila protein Jumu binds N6-methyladenine (6mA)-marked DNA and acts as a maternal factor to regulate the maternal-to-zygotic transition and finds that zelda encoding the pioneer factor Zelda is marked by 6mA. Genetic assays suggest that Jumu controls the proper zygotic genome activation in early embryos, at least in part, by regulating zelda expression. (PMID:31101825)
• The Drosophila Forkhead/Fox transcription factor Jumeau mediates specific cardiac progenitor cell divisions by regulating expression of the kinesin Nebbish. (PMID:33547352)
• Jumu is required for the activation of JAK/STAT in Drosophila lymph gland development and epidermal wounds. (PMID:34999256)
• Thus, the Met-326Ile variant of p85alpha is functional for intracellular signaling and adipocyte differentiation but has small alterations in protein expression and activity that could play a role in modifying insulin action. (PMID:11842213)
• Expression of a mutated in a Hodgkin’s lymphoma-derived cell line; the first detection in human hematopoietic cells further underlining a potential role of PI3-kinase/Akt signaling in human leukemogenesis (PMID:11986952)
• The p85 subunit of PI 3-kinase mediates GPIb-related activation signals and activates Src independently of the enzymatic activity of PI 3- kinase. (PMID:12393736)
• Gene expression of full-length p85alpha is increased in skeletal muscle from type 2 diabetics, this is not reflected by increased protein. Defects in PI 3-kinase activity are likely due to impaired activation of the enzyme. (PMID:12397383)
• The isoleucine variant of codon 326 of the p85alpha subunit of PI3-K might be associated with decreased risk of Prostate Cancer. (PMID:12582030)
• p55gamma binds to Rb and modification of this association can lead to cell cycle arrest (PMID:12588990)
• protein whose expression is deregulated in the epidermis of the elderly. (PMID:12644569)
• the role of p85-ALPHA in the survival of cancer cells that express wild-type PTEN (PMID:12714585)
• PI3K has a novel role as a bikunin target gene on uPA up-regulation and invasion (PMID:14597629)
• These findings reveal key events of the phosphatidylinositol 3-kinase pathway that play distinct roles to maintain tissue polarity and that when disrupted are instrumental in the malignant breast tumor phenotype. (PMID:14769856)
• coupling of Gab1 to PI3K is important for biological responses in RET-expressing cells (PMID:15351743)
• Data suggest that SLP-76 may play a role in signaling pathways by interacting with the p85 subunit of phosphoinositide 3-kinase (PI3K). (PMID:15388330)
• p110gamma and p85alpha class Ia phosphoinositide 3-kinase (PI3K) subunits play roles in generating the antiapoptotic and chemoresistant phenotype associated with accelerated local tumor recurrence (PMID:15741161)
• PI3K regulates cell cycle progression and cell proliferation in human gastric tumor cells via Rb-mediated pathway; effect mediated through direct association with Rb via N-terminal end of its p55 kDa regulatory subunits and modulating Rb-E2F interactions (PMID:15809724)
• WAVE3-mediated migration in MDA-MB-231 cells via lamellipodia formation is activated downstream of PI3K and induced by PDGF (PMID:15826941)
• calcium activates PLC-gamma1 via increased PIP3 formation mediated by c-src- and fyn-activated PI3K (PMID:15872086)
• the nSH2 domain of the p85 regulatory subumit is responsible for p110 regulatory contacts, and its disruption leads to constitutive p110 activity (PMID:15932879)
• Inhibitors may provide an alternative route to effective PI3K pathway inhibition for breast cancer treatment. (PMID:16168140)
• the signals induced by integrin alpha6beta1 modulate at the level of PI3K and Cdc42 activity to allow platelets to actively form filopodia (PMID:16228294)
• CD21 activation triggered Cbl tyrosine phosphorylation, which interacts with SH2 domains of p85 subunit, SH2 domains of Crk-L and with tyrosine phosphorylated Syk kinase. CD21 activation triggers dissociation of Cbl-Vav complex. (PMID:16289966)
• SHP-2 recruitment to p85 is required for IGF-I-stimulated association of the p85/p110 complex with insulin receptor substrate-1 and for the subsequent activation of the PI-3 kinase pathway leading to increased cell migration (PMID:16306077)
• the PI3-K pathway negatively regulates TGF-beta/Smad signaling in neuroblastoma cells (PMID:16412560)
• increased expression of p85alpha may be one of the earliest molecular alterations in the mechanism of the insulin resistance associated with overfeeding (PMID:16491394)
• MyD88 bridges TLR5 engagement to PI3K activation in response to flagellin (PMID:16644730)
• Gab1 thus appears as a primary actor in coupling VEGFR-2 to PI3K/Akt, recruited through an amplification loop involving PtdIns(3,4,5)P3 and its PH domain (PMID:16787925)
• Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent p85 PI3K and Akt and Erk activation (PMID:16844778)
• direct interactions between native Syk and PI3K proteins are differentially regulated during FcgammaR phagocytosis and endocytosis. (PMID:16921024)
• It has recently been shown that Akt activation is associated with a worse outcome among endocrine treated breast cancer patients and that it also inhibits the progesterone receptor (PR) expression via the PI3K/Akt pathway in breast cancer cells. (PMID:17006756)
• autotaxin induces uPA expression via the Gi-PI3K-Akt-NF-kappaB signaling pathway that might be critical for autotaxin-induced tumor cell invasion and metastasis (PMID:17013094)
• Association of single nucleotide polymorphisms with serum leptin and body fat may reflect a diminished ability of this enzyme to signal in ersponse to leptin. (PMID:17016694)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pik3r1	ENSDARG00000038524
mus_musculus	Pik3r1	ENSMUSG00000041417
rattus_norvegicus	Pik3r1	ENSRNOG00000018903

Paralogs (2): PIK3R2 (ENSG00000105647), PIK3R3 (ENSG00000117461)

Protein

Protein identifiers

Phosphatidylinositol 3-kinase regulatory subunit alpha — P27986 (reviewed: P27986)

Alternative names: Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha

All UniProt accessions (18): A0A2X0SFG1, A0A8V8TL10, A0A8V8TL14, A0A8V8TL31, A0A8V8TLE6, A0A8V8TLF1, A0A8V8TLF7, A0A8V8TME9, A0A8V8TMF4, A0A8V8TMF9, B3KWZ7, E5RGI8, E5RHI0, E5RJY0, E5RK66, P27986, H0YB27, H0YBC2

UniProt curated annotations — full annotation on UniProt →

Function. Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling. Modulates the cellular response to ER stress by promoting nuclear translocation of XBP1 isoform 2 in a ER stress- and/or insulin-dependent manner during metabolic overloading in the liver and hence plays a role in glucose tolerance improvement.

Subunit / interactions. Heterodimer of a regulatory subunit PIK3R1 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD). Interacts (via SH2 domains) with CCDC88A/GIV (tyrosine-phosphorylated form); the interaction enables recruitment of PIK3R1 to the EGFR receptor, enhancing PI3K activity and cell migration. Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts with PIK3R2; the interaction is dissociated in an insulin-dependent manner. Interacts with XBP1 isoform 2; the interaction is direct and induces translocation of XBP1 isoform 2 into the nucleus in a ER stress- and/or insulin-dependent but PI3K-independent manner. Interacts with FER. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated). Interacts with PTK2/FAK1. Interacts with phosphorylated TOM1L1. Interacts with phosphorylated LIME1 upon TCR and/or BCR activation. Interacts with SOCS7. Interacts with RUFY3. Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts with LYN (via SH3 domain); this enhances enzyme activity. Interacts with phosphorylated LAT, LAX1 and TRAT1 upon TCR activation. Interacts with CBLB. The SH2 domains interact with the YTHM motif of phosphorylated INSR in vitro. Also interacts with tyrosine-phosphorylated IGF1R in vitro. Interacts with CD28 and CD3Z upon T-cell activation. Interacts with IRS1, IRS2 and phosphorylated IRS4, as well as with NISCH and HCST. Interacts with FASLG, KIT and BCR. Interacts with AXL, FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated). Interacts with FGR and HCK. Interacts with PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine phosphorylated). Interacts with ERBB4 (phosphorylated). Interacts with NTRK1 (phosphorylated upon ligand-binding). Interacts with FAM83B; activates the PI3K/AKT signaling cascade. Interacts with APPL1 and APPL2. Interacts with SRC. Interacts with ALOX5; this interaction bridges ALOX5 with CD40 after CD40 ligation in B cells and leads to the production of reactive oxygen species (ROS). Interacts with TYK2. Interacts with nephrin NPHN1; the interaction is reduced by high glucose levels. Interacts with CASP8 (phosphorylated on Tyr-380). Interacts with CD28. Interacts with ICOS. (Microbial infection) Interacts with HIV-1 Nef to activate the Nef associated p21-activated kinase (PAK). This interaction depends on the C-terminus of both proteins and leads to increased production of HIV. (Microbial infection) Interacts with HCV NS5A. (Microbial infection) Interacts with herpes simplex virus 1 UL46; this interaction activates the PI3K/AKT pathway. (Microbial infection) Interacts with herpes simplex virus 1 UL46 and varicella virus ORF12; this interaction activates the PI3K/AKT pathway.

Tissue specificity. Isoform 2 is expressed in skeletal muscle and brain, and at lower levels in kidney and cardiac muscle. Isoform 2 and isoform 4 are present in skeletal muscle (at protein level).

Post-translational modifications. Polyubiquitinated in T-cells by CBLB; which does not promote proteasomal degradation but impairs association with CD28 and CD3Z upon T-cell activation. In adipose tissue, polyubiquitinated by the BCR(KBTBD2) E3 ubiquitin ligase complex; recognized by KBTBD2 through the SH2 domains, undergoes ‘Lys-48’-linked polyubiquitination leading to its degradation. Phosphorylated. Tyrosine phosphorylated in response to signaling by FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylated by CSF1R. Phosphorylated by ERBB4. Phosphorylated on tyrosine residues by TEK/TIE2. Dephosphorylated by PTPRJ. Phosphorylated by PIK3CA at Ser-608; phosphorylation is stimulated by insulin and PDGF. The relevance of phosphorylation by PIK3CA is however unclear. Phosphorylated in response to KIT and KITLG/SCF. Phosphorylated by FGR.

Disease relevance. Agammaglobulinemia 7, autosomal recessive (AGM7) [MIM:615214] A primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life. The disease is caused by variants affecting the gene represented in this entry. SHORT syndrome (SHORTS) [MIM:269880] A rare, multisystem disease characterized by short stature, anomalies of the anterior chamber of the eye, characteristic facial features such as triangular facies, lack of facial fat, and hypoplastic nasal alae with overhanging columella, partial lipodystrophy, hernias, hyperextensibility, and delayed dentition. The clinical phenotype can include insulin resistance, nephrocalcinosis, and hearing deficits. Developmental milestones and cognition are normal. The disease is caused by variants affecting the gene represented in this entry. Immunodeficiency 36 with lymphoproliferation (IMD36) [MIM:616005] A primary immunodeficiency characterized by impaired B-cell function, hypogammaglobulinemia and recurrent infections. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The SH3 domain mediates the binding to CBLB, and to HIV-1 Nef.

Similarity. Belongs to the PI3K p85 subunit family.

Isoforms (5)

UniProt ID	Names	Canonical?
P27986-1	1	yes
P27986-2	2, AS53
P27986-3	3, p46
P27986-4	4, p85I
P27986-5	5

RefSeq proteins (4): NP_001229395, NP_852556, NP_852664, NP_852665 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR000980	SH2	Domain
IPR001452	SH3_domain	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR032498	PI3K_P85_iSH2	Domain
IPR035020	PI3kinase_P85_cSH2	Domain
IPR035022	PI3kinase_P85_nSH2	Domain
IPR035591	PI3K_p85alpha_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR044124	ISH2_PIK3R1	Domain

Pfam: PF00017, PF00620, PF16454

Enzyme classification (BRENDA):

• EC 2.7.1.153 — phosphatidylinositol-4,5-bisphosphate 3-kinase (BRENDA: 12 organisms, 48 substrates, 96 inhibitors, 1 Km, 0 kcat entries)

UniProt features (91 total): helix 32, strand 23, turn 7, modified residue 6, splice variant 6, sequence variant 6, domain 4, sequence conflict 2, initiator methionine 1, chain 1, region of interest 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

105 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5GJI	X-RAY DIFFRACTION	0.9
5AUL	X-RAY DIFFRACTION	1.1
7CIO	X-RAY DIFFRACTION	1.1
7RNS	X-RAY DIFFRACTION	1.14
3I5R	X-RAY DIFFRACTION	1.7
1H9O	X-RAY DIFFRACTION	1.79
2IUG	X-RAY DIFFRACTION	1.89
1PBW	X-RAY DIFFRACTION	2
1PHT	X-RAY DIFFRACTION	2
2IUH	X-RAY DIFFRACTION	2
4JPS	X-RAY DIFFRACTION	2.2
7PG5	X-RAY DIFFRACTION	2.2
6PYR	X-RAY DIFFRACTION	2.21
8SBC	X-RAY DIFFRACTION	2.3
4WAF	X-RAY DIFFRACTION	2.39
2IUI	X-RAY DIFFRACTION	2.4
2V1Y	X-RAY DIFFRACTION	2.4
7TZ7	X-RAY DIFFRACTION	2.41
8DCP	ELECTRON MICROSCOPY	2.41
7PG6	X-RAY DIFFRACTION	2.5
5FI4	X-RAY DIFFRACTION	2.5
5UK8	X-RAY DIFFRACTION	2.5
4L23	X-RAY DIFFRACTION	2.5
8TSA	X-RAY DIFFRACTION	2.51
6PYU	X-RAY DIFFRACTION	2.54
5XGI	X-RAY DIFFRACTION	2.56
4L1B	X-RAY DIFFRACTION	2.59
8V8V	X-RAY DIFFRACTION	2.61
4ZOP	X-RAY DIFFRACTION	2.62
8TSD	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P27986-F1	83.76	0.52

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): 151 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Post-translational modifications (6): 154, 279, 467, 580, 608, 2

Function

Pathways and Gene Ontology

Reactome pathways

78 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-112399	IRS-mediated signalling
R-HSA-114604	GPVI-mediated activation cascade
R-HSA-1236382	Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
R-HSA-1250342	PI3K events in ERBB4 signaling
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1266695	Interleukin-7 signaling
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-1660499	Synthesis of PIPs at the plasma membrane
R-HSA-180292	GAB1 signalosome
R-HSA-1839117	Signaling by cytosolic FGFR1 fusion mutants
R-HSA-186763	Downstream signal transduction
R-HSA-1963642	PI3K events in ERBB2 signaling
R-HSA-198203	PI3K/AKT activation
R-HSA-201556	Signaling by ALK
R-HSA-202424	Downstream TCR signaling
R-HSA-2029485	Role of phospholipids in phagocytosis
R-HSA-210993	Tie2 Signaling
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-2424491	DAP12 signaling
R-HSA-2730905	Role of LAT2/NTAL/LAB on calcium mobilization
R-HSA-373753	Nephrin family interactions
R-HSA-389357	CD28 dependent PI3K/Akt signaling
R-HSA-416476	G alpha (q) signalling events
R-HSA-430116	GP1b-IX-V activation signalling
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-512988	Interleukin-3, Interleukin-5 and GM-CSF signaling
R-HSA-5637810	Constitutive Signaling by EGFRvIII
R-HSA-5654689	PI-3K cascade:FGFR1
R-HSA-5654695	PI-3K cascade:FGFR2

MSigDB gene sets: 1394 (showing top): PID_BCR_5PATHWAY, PID_SHP2_PATHWAY, GOBP_MYELOID_CELL_DIFFERENTIATION, BIOCARTA_GCR_PATHWAY, TGGTGCT_MIR29A_MIR29B_MIR29C, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, BIOCARTA_PTEN_PATHWAY, RRAGTTGT_UNKNOWN, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION

GO Biological Process (47): protein polyubiquitination (GO:0000209), intracellular glucose homeostasis (GO:0001678), negative regulation of cell-matrix adhesion (GO:0001953), positive regulation of leukocyte migration (GO:0002687), transcription by RNA polymerase II (GO:0006366), protein import into nucleus (GO:0006606), immune response (GO:0006955), insulin receptor signaling pathway (GO:0008286), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), positive regulation of lamellipodium assembly (GO:0010592), cytokine-mediated signaling pathway (GO:0019221), B cell differentiation (GO:0030183), T cell differentiation (GO:0030217), osteoclast differentiation (GO:0030316), positive regulation of tumor necrosis factor production (GO:0032760), cellular response to insulin stimulus (GO:0032869), positive regulation of RNA splicing (GO:0033120), regulation of toll-like receptor 4 signaling pathway (GO:0034143), substrate adhesion-dependent cell spreading (GO:0034446), cellular response to UV (GO:0034644), response to endoplasmic reticulum stress (GO:0034976), interleukin-18-mediated signaling pathway (GO:0035655), natural killer cell mediated cytotoxicity (GO:0042267), positive regulation of protein import into nucleus (GO:0042307), negative regulation of apoptotic process (GO:0043066), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), negative regulation of osteoclast differentiation (GO:0045671), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of D-glucose import across plasma membrane (GO:0046326), phosphatidylinositol phosphate biosynthetic process (GO:0046854), insulin-like growth factor receptor signaling pathway (GO:0048009), positive regulation of smooth muscle cell proliferation (GO:0048661), protein stabilization (GO:0050821), positive regulation of filopodium assembly (GO:0051491), negative regulation of stress fiber assembly (GO:0051497), growth hormone receptor signaling pathway (GO:0060396), T follicular helper cell differentiation (GO:0061470), myeloid leukocyte migration (GO:0097529), positive regulation of focal adhesion disassembly (GO:0120183)

GO Molecular Function (22): phosphotyrosine residue binding (GO:0001784), transmembrane receptor protein tyrosine kinase adaptor activity (GO:0005068), GTPase activator activity (GO:0005096), insulin receptor binding (GO:0005158), insulin-like growth factor receptor binding (GO:0005159), neurotrophin TRKA receptor binding (GO:0005168), kinase activator activity (GO:0019209), protein phosphatase binding (GO:0019903), phosphatidylinositol 3-kinase regulator activity (GO:0035014), phosphatidylinositol 3-kinase regulatory subunit binding (GO:0036312), ErbB-3 class receptor binding (GO:0043125), phosphatidylinositol 3-kinase binding (GO:0043548), insulin binding (GO:0043559), insulin receptor substrate binding (GO:0043560), 1-phosphatidylinositol-3-kinase regulator activity (GO:0046935), protein heterodimerization activity (GO:0046982), phosphatidylinositol kinase activity (GO:0052742), enzyme-substrate adaptor activity (GO:0140767), phosphatidylinositol 3-kinase activator activity (GO:0141038), protein binding (GO:0005515), kinase activity (GO:0016301), kinase regulator activity (GO:0019207)

GO Cellular Component (11): nucleus (GO:0005634), cytoplasm (GO:0005737), cis-Golgi network (GO:0005801), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), phosphatidylinositol 3-kinase complex (GO:0005942), phosphatidylinositol 3-kinase complex, class IA (GO:0005943), membrane (GO:0016020), perinuclear region of cytoplasm (GO:0048471), perinuclear endoplasmic reticulum membrane (GO:1990578)

Reactome top-level categories

Rollup of top-20 pathways:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	2
IRS-mediated signalling	1
IRS-related events triggered by IGF1R	1
Insulin receptor signalling cascade	1
Platelet activation, signaling and aggregation	1
Signaling by Ligand-Responsive EGFR Variants in Cancer	1
Signaling by ERBB4	1
Intracellular signaling by second messengers	1
Signaling by Interleukins	1
PI Metabolism	1
Signaling by EGFR	1
FGFR1 mutant receptor activation	1
Signaling by PDGF	1
Signaling by ERBB2	1
Signaling by NTRK1 (TRKA)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
signaling receptor binding	3
kinase regulator activity	3
protein binding	3
cell surface receptor protein tyrosine kinase signaling pathway	2
lymphocyte differentiation	2
enzyme activator activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
protein ubiquitination	1
glucose homeostasis	1
intracellular chemical homeostasis	1
regulation of cell-matrix adhesion	1
cell-matrix adhesion	1
negative regulation of cell-substrate adhesion	1
positive regulation of immune system process	1
regulation of leukocyte migration	1
positive regulation of cell migration	1
leukocyte migration	1
DNA-templated transcription	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
immune system process	1
response to stimulus	1
cellular response to insulin stimulus	1
extrinsic apoptotic signaling pathway	1
DNA damage response	1
intrinsic apoptotic signaling pathway	1
regulation of lamellipodium assembly	1
lamellipodium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
positive regulation of lamellipodium organization	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
B cell activation	1
T cell activation	1
myeloid leukocyte differentiation	1
tumor necrosis factor production	1

Protein interactions and networks

STRING

3484 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIK3R1	PIK3CA	P42336	998
PIK3R1	PIK3CB	P42338	997
PIK3R1	PIK3CD	O00329	996
PIK3R1	IRS1	P35568	995
PIK3R1	PIK3CG	P48736	988
PIK3R1	GRB2	P29354	975
PIK3R1	ESR1	P03372	971
PIK3R1	ZFPM2	Q8WW38	961
PIK3R1	PIK3R2	O00459	959
PIK3R1	PTEN	P60484	944
PIK3R1	AKT1	P31749	914
PIK3R1	EGFR	P00533	901
PIK3R1	PDGFRB	P09619	900
PIK3R1	TP53	P04637	853
PIK3R1	SRC	P12931	848

IntAct

783 interactions, top by confidence:

A	B	Type	Score
PIK3CA	PIK3R1	psi-mi:“MI:0407”(direct interaction)	0.960
PIK3CA	PIK3R1	psi-mi:“MI:0915”(physical association)	0.960
PIK3R1	PIK3CA	psi-mi:“MI:0915”(physical association)	0.960
ERBB2	EGFR	psi-mi:“MI:0914”(association)	0.950
PIK3R1	ERBB3	psi-mi:“MI:0915”(physical association)	0.920
GRB2	PIK3R1	psi-mi:“MI:0915”(physical association)	0.900
PIK3CA	PIK3R2	psi-mi:“MI:0914”(association)	0.900
CD28	PIK3R1	psi-mi:“MI:0914”(association)	0.900
PIK3R1	PIK3CD	psi-mi:“MI:0407”(direct interaction)	0.890
PIK3R1	PIK3CD	psi-mi:“MI:0915”(physical association)	0.890
ESR1	SRC	psi-mi:“MI:0914”(association)	0.850
SRC	ESR1	psi-mi:“MI:0914”(association)	0.850
PIK3R1	PIK3CB	psi-mi:“MI:0915”(physical association)	0.840
PIK3R1	CDC42	psi-mi:“MI:0914”(association)	0.790
NS	PIK3R2	psi-mi:“MI:0914”(association)	0.750
NS	PIK3R1	psi-mi:“MI:0915”(physical association)	0.660
JMJD6	ESR1	psi-mi:“MI:0914”(association)	0.650
	PIK3R1	psi-mi:“MI:0414”(enzymatic reaction)	0.620
ICOS	PIK3R1	psi-mi:“MI:0914”(association)	0.620

BioGRID (901): PIK3R1 (Affinity Capture-Western), NCL (Affinity Capture-Western), PIK3R1 (Two-hybrid), PIK3R1 (Affinity Capture-Western), PIK3R1 (Far Western), PIK3R1 (Far Western), SQSTM1 (Affinity Capture-Western), PIK3CA (Affinity Capture-Western), PIK3CB (Affinity Capture-Western), PIK3R1 (Affinity Capture-Western), PIK3R1 (Affinity Capture-MS), PIK3R1 (Affinity Capture-MS), PIK3R1 (Affinity Capture-MS), PIK3R1 (Affinity Capture-MS), PIK3R1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JTR4, A1A4S6, A2AWA9, A4FUD6, A4II46, A6H6A9, A6QNS3, A6QQZ7, O60890, P09851, P0CAX5, P20936, P23727, P26450, P27986, P50904, Q08DP6, Q12979, Q5R372, Q5R5M3, Q5R685, Q5R6F2, Q5R8I6, Q5RCC1, Q5RCW6, Q5SSL4, Q5T2T1, Q5U2Y3, Q5ZJ17, Q5ZLX4, Q5ZMW5, Q62696, Q63787, Q6Y5D8, Q6ZQ82, Q7YQL5, Q7YQL6, Q8AVG0, Q8BPU7, Q8K0F1

Diamond homologs: G5ECJ6, O00459, O08908, O14508, O14544, O35717, O46404, O88582, P00519, P00520, P00521, P10447, P14234, P15498, P23726, P23727, P26450, P27986, P41242, P41243, P42679, P42684, P54100, P62993, P62994, Q08012, Q08DN7, Q45FX5, Q4JIM5, Q54RB7, Q5R4J7, Q5R685, Q5RCM6, Q60631, Q62662, Q63787, Q63788, Q63789, Q64143, Q6P6U0

SIGNOR signaling

43 interactions.

A	Effect	B	Mechanism
CBL	down-regulates	PIK3R1	ubiquitination
EGFR	up-regulates	PIK3R1	binding
ESR1	up-regulates	PIK3R1	binding
PTPRJ	down-regulates	PIK3R1	dephosphorylation
IGF1R	up-regulates	PIK3R1	binding
GNAS	up-regulates	PIK3R1	binding
PIK3AP1	up-regulates	PIK3R1	binding
TGFBR2	“up-regulates activity”	PIK3R1	binding
TGFB1	“up-regulates activity”	PIK3R1	binding
TGFBR2	up-regulates	PIK3R1	binding
TGFBR1	up-regulates	PIK3R1	binding
LAT	“up-regulates activity”	PIK3R1	binding
DAB2IP	“down-regulates activity”	PIK3R1	binding
PIK3R1	“form complex”	PI3K	binding
KDR	“up-regulates activity”	PIK3R1	binding
BCAR1	“up-regulates activity”	PIK3R1	binding
ICOS	“up-regulates activity”	PIK3R1	binding
CBLB	“down-regulates quantity by destabilization”	PIK3R1	polyubiquitination
PRKD1	“up-regulates activity”	PIK3R1	phosphorylation
PTK2	up-regulates	PIK3R1	binding
LY294002	down-regulates	PIK3R1	“chemical inhibition”
CD19	“up-regulates activity”	PIK3R1	binding
PPM1A	“up-regulates activity”	PIK3R1	dephosphorylation
GRB10	“up-regulates activity”	PIK3R1	binding
FLT3	“up-regulates activity”	PIK3R1
IRS1	“up-regulates activity”	PIK3R1	binding
PIK3R1	“up-regulates quantity”	PIP3
TEK	“up-regulates activity”	PIK3R1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 146 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
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	9	41.7×	1e-10
Regulation of signaling by CBL	8	35.5×	3e-09
Interleukin-2 family signaling	6	34.0×	7e-07
Interleukin receptor SHC signaling	9	32.8×	6e-10
Regulation of KIT signaling	6	32.2×	9e-07
Role of LAT2/NTAL/LAB on calcium mobilization	6	32.2×	9e-07
Signaling by CSF1 (M-CSF) in myeloid cells	10	30.9×	1e-10
PI3K events in ERBB2 signaling	5	30.0×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
phosphatidylinositol-mediated signaling	5	25.6×	3e-04
positive regulation of Rac protein signal transduction	5	23.7×	4e-04
leukocyte migration	5	22.8×	4e-04
T cell costimulation	7	19.1×	2e-05
insulin-like growth factor receptor signaling pathway	5	18.1×	9e-04
B cell receptor signaling pathway	6	17.6×	3e-04
phosphatidylinositol 3-kinase/protein kinase B signal transduction	11	16.9×	6e-08
epidermal growth factor receptor signaling pathway	9	16.3×	2e-06

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 15 cancer types — ACYC, BRCA, CHOL, COAD, COADREAD, GB, GBM, HNSC, LGGNOS, LUSC, OVT, PRAD…(+3 more).

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	43
Likely pathogenic	31
Uncertain significance	308
Likely benign	240
Benign	33

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072261	NM_181523.3(PIK3R1):c.901C>T (p.Arg301Ter)	Pathogenic
1370470	NM_181523.3(PIK3R1):c.484C>T (p.Arg162Ter)	Pathogenic
1393351	NM_181523.3(PIK3R1):c.1344dup (p.Leu449fs)	Pathogenic
1452339	NM_181523.3(PIK3R1):c.450C>G (p.Tyr150Ter)	Pathogenic
156008	NM_181523.3(PIK3R1):c.1425+1G>T	Pathogenic
156009	NM_181523.3(PIK3R1):c.1425+1G>C	Pathogenic
1686070	NM_181523.3(PIK3R1):c.916+1G>A	Pathogenic
2104788	NM_181523.3(PIK3R1):c.1350_1360del (p.Glu451fs)	Pathogenic
2126685	NM_181523.3(PIK3R1):c.1072C>T (p.Arg358Ter)	Pathogenic
2691258	NM_181523.3(PIK3R1):c.1718T>C (p.Leu573Pro)	Pathogenic
2951379	NM_181523.3(PIK3R1):c.1650_1674del (p.Lys551fs)	Pathogenic
2952024	NM_181523.3(PIK3R1):c.1314_1317del (p.Glu439fs)	Pathogenic
2952766	NM_181523.3(PIK3R1):c.1306_1313del (p.Val436fs)	Pathogenic
3748560	NM_181523.3(PIK3R1):c.1156C>T (p.Arg386Ter)	Pathogenic
376064	NM_181523.3(PIK3R1):c.1126G>A (p.Gly376Arg)	Pathogenic
376261	NM_181523.3(PIK3R1):c.1690A>G (p.Asn564Asp)	Pathogenic
376263	NM_181523.3(PIK3R1):c.1748_1750delGGT	Pathogenic
3767319	NM_181523.3(PIK3R1):c.1957A>T (p.Lys653Ter)	Pathogenic
3774503	NM_181523.3(PIK3R1):c.1735delinsTTGATGTAAGTATTTGA (p.Gln579delinsLeuMetTer)	Pathogenic
3774527	NM_181523.3(PIK3R1):c.1746-2A>T	Pathogenic
379688	NM_181523.3(PIK3R1):c.1042C>T (p.Arg348Ter)	Pathogenic
3897534	PIK3R1, 38-BP DEL, IVS10AS	Pathogenic
3901222	NM_181523.3(PIK3R1):c.703C>T (p.Gln235Ter)	Pathogenic
3906270	NM_181523.3(PIK3R1):c.244dup (p.Ile82fs)	Pathogenic
446497	NM_181523.3(PIK3R1):c.1425+2T>A	Pathogenic
446498	NM_181523.3(PIK3R1):c.1425+2T>G	Pathogenic
446499	NM_181523.3(PIK3R1):c.1425+2_1425+3del	Pathogenic
446500	NM_181523.3(PIK3R1):c.1300-1G>C	Pathogenic
4785500	NM_181523.3(PIK3R1):c.1756C>T (p.Gln586Ter)	Pathogenic
4787131	NM_181523.3(PIK3R1):c.521del (p.Leu174fs)	Pathogenic

SpliceAI

2428 predictions. Top by Δscore:

Variant	Effect	Δscore
5:68215930:G:GT	donor_gain	1.0000
5:68274011:GTG:G	donor_gain	1.0000
5:68279596:TCCTA:T	acceptor_loss	1.0000
5:68279597:CCTAG:C	acceptor_loss	1.0000
5:68279598:CTA:C	acceptor_loss	1.0000
5:68279599:TAG:T	acceptor_loss	1.0000
5:68279600:A:AG	acceptor_gain	1.0000
5:68279600:A:T	acceptor_loss	1.0000
5:68279601:G:GT	acceptor_gain	1.0000
5:68279601:GA:G	acceptor_gain	1.0000
5:68279601:GAT:G	acceptor_gain	1.0000
5:68279601:GATA:G	acceptor_gain	1.0000
5:68279601:GATAC:G	acceptor_gain	1.0000
5:68280518:A:AG	acceptor_gain	1.0000
5:68280519:A:G	acceptor_gain	1.0000
5:68280520:A:G	acceptor_gain	1.0000
5:68280524:GTA:G	acceptor_loss	1.0000
5:68280525:TAG:T	acceptor_loss	1.0000
5:68280526:A:AG	acceptor_gain	1.0000
5:68280526:A:T	acceptor_loss	1.0000
5:68280527:G:GG	acceptor_gain	1.0000
5:68280527:GAA:G	acceptor_gain	1.0000
5:68280925:A:AG	acceptor_gain	1.0000
5:68280926:G:GG	acceptor_gain	1.0000
5:68280926:GCT:G	acceptor_gain	1.0000
5:68280926:GCTCT:G	acceptor_gain	1.0000
5:68281002:ACCAG:A	donor_loss	1.0000
5:68281003:CCAG:C	donor_loss	1.0000
5:68281004:CAGG:C	donor_loss	1.0000
5:68281005:AGG:A	donor_loss	1.0000

AlphaMissense

4778 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:68226764:T:C	L30S	1.000
5:68226838:T:A	W55R	1.000
5:68226838:T:C	W55R	1.000
5:68226881:T:C	F69S	1.000
5:68292339:T:A	W333R	1.000
5:68292339:T:C	W333R	1.000
5:68292341:G:C	W333C	1.000
5:68292341:G:T	W333C	1.000
5:68292342:T:C	Y334H	1.000
5:68292342:T:G	Y334D	1.000
5:68292343:A:C	Y334S	1.000
5:68292345:T:A	W335R	1.000
5:68292345:T:C	W335R	1.000
5:68292347:G:C	W335C	1.000
5:68292347:G:T	W335C	1.000
5:68292349:G:T	G336V	1.000
5:68292360:A:G	R340G	1.000
5:68292360:A:T	R340W	1.000
5:68292361:G:C	R340T	1.000
5:68292361:G:T	R340M	1.000
5:68293101:G:C	R340S	1.000
5:68293101:G:T	R340S	1.000
5:68293108:G:C	V343L	1.000
5:68293108:G:T	V343L	1.000
5:68293113:T:A	N344K	1.000
5:68293113:T:G	N344K	1.000
5:68293121:T:A	L347H	1.000
5:68293121:T:C	L347P	1.000
5:68293124:G:C	R348P	1.000
5:68293135:G:C	D352H	1.000

dbSNP variants (sampled 300 via entrez): RS1000055479 (5:68237908 A>G), RS1000086568 (5:68265691 G>A), RS1000105055 (5:68234823 A>G), RS1000113963 (5:68279548 A>G), RS1000269929 (5:68286075 C>T), RS1000271489 (5:68227705 C>T), RS1000280059 (5:68300538 A>C), RS1000280677 (5:68253781 C>T), RS1000292757 (5:68238793 A>C), RS1000317384 (5:68299895 C>T), RS1000327442 (5:68299489 GTC>G), RS1000367546 (5:68254469 T>C), RS1000374870 (5:68247638 G>T), RS1000444454 (5:68292799 A>G), RS1000445421 (5:68246913 A>G)

Disease associations

OMIM: gene MIM:171833 | disease phenotypes: MIM:269880, MIM:615214, MIM:616005, MIM:612918, MIM:615513, MIM:114500

GenCC curated gene-disease

Disease	Classification	Inheritance
SHORT syndrome	Definitive	Autosomal dominant
immunodeficiency 36 with lymphoproliferation	Definitive	Autosomal dominant
agammaglobulinemia 7, autosomal recessive	Strong	Autosomal recessive
PIK3R1-related immunodeficiency and SHORT syndrome	Strong	Autosomal dominant
autosomal agammaglobulinemia	Supportive	Autosomal dominant
activated PI3K-delta syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
PIK3R1-related immunodeficiency and SHORT syndrome	Definitive	AD
agammaglobulinemia 7, autosomal recessive	Limited	AR

Mondo (13): SHORT syndrome (MONDO:0010026), agammaglobulinemia 7, autosomal recessive (MONDO:0014083), immunodeficiency 36 with lymphoproliferation (MONDO:0014453), activated PI3K-delta syndrome (MONDO:0018338), prostate cancer (MONDO:0008315), CLOVES syndrome (MONDO:0013038), overgrowth syndrome (MONDO:0019716), vascular malformation (MONDO:0024291), immunodeficiency 14 (MONDO:0014222), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042), colorectal cancer (MONDO:0005575), autosomal agammaglobulinemia (MONDO:0011096), PIK3R1-related immunodeficiency and SHORT syndrome (MONDO:1060136)

Orphanet (9): SHORT syndrome (Orphanet:3163), Activated PI3K-delta syndrome (Orphanet:397596), Activated PI3K-delta syndrome 2 (Orphanet:693681), Familial prostate cancer (Orphanet:1331), CLOVES syndrome (Orphanet:140944), Overgrowth syndrome (Orphanet:93460), Activated PI3K-delta syndrome 1 (Orphanet:693661), Multiple congenital anomalies/dysmorphic syndrome (Orphanet:68341), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

144 total (30 of 144 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000138	Ovarian cyst
HP:0000164	Abnormality of the dentition
HP:0000218	High palate
HP:0000246	Sinusitis
HP:0000271	Abnormality of the face
HP:0000272	Malar flattening
HP:0000277	Abnormal mandible morphology
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000331	Short chin
HP:0000336	Prominent supraorbital ridges
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000389	Chronic otitis media
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000483	Astigmatism
HP:0000485	Megalocornea
HP:0000490	Deeply set eye
HP:0000501	Glaucoma
HP:0000506	Telecanthus
HP:0000509	Conjunctivitis
HP:0000518	Cataract

GWAS associations

37 associations (top):

Study	Trait	p-value
GCST001868_5	Alzheimer’s disease biomarkers	2.000000e-06
GCST001973_14	Menarche (age at onset)	4.000000e-07
GCST003372_47	Glomerular filtration rate (creatinine)	2.000000e-07
GCST003379_3	Bone mineral density (hip)	2.000000e-07
GCST003853_5	Hip minimal joint space width	4.000000e-09
GCST004292_19	Glomerular filtration rate (creatinine)	2.000000e-09
GCST004602_35	Mean corpuscular volume	2.000000e-15
GCST004621_84	Red cell distribution width	2.000000e-10
GCST004630_146	Mean corpuscular hemoglobin	4.000000e-17
GCST005316_580	Intelligence (MTAG)	2.000000e-08
GCST005790_98	Rosacea symptom severity	7.000000e-06
GCST007159_23	Corneal astigmatism	7.000000e-06
GCST007344_106	Estimated glomerular filtration rate	8.000000e-10
GCST007344_63	Estimated glomerular filtration rate	1.000000e-07
GCST007490_10	Anthropometric traits (multi-trait analysis)	8.000000e-15
GCST008058_182	Estimated glomerular filtration rate	1.000000e-30
GCST008059_137	Estimated glomerular filtration rate	3.000000e-29
GCST008362_221	Birth weight	2.000000e-11
GCST008363_42	Offspring birth weight	6.000000e-06
GCST008839_387	Height	8.000000e-18
GCST009152_2	Triglyceride levels	1.000000e-15
GCST009380_13	Type 2 diabetes (adjusted for BMI)	1.000000e-09
GCST010242_254	HDL cholesterol levels	1.000000e-09
GCST010244_233	Triglyceride levels	3.000000e-18
GCST010577_21	Crohn’s disease	2.000000e-06
GCST011344_6	Body fat percentage and HDL-C (pairwise)	1.000000e-10
GCST011393_2	Leg fat mass (lean adjusted)	5.000000e-07
GCST011394_2	Leg fat mass and leg lean mass (pleiotropy)	6.000000e-07
GCST90000025_39	Appendicular lean mass	1.000000e-20
GCST90002390_129	Mean corpuscular hemoglobin	7.000000e-26

EFO canonical traits (19, from GWAS)

EFO ID	Trait name
EFO:0005194	amyloid-beta measurement
EFO:0004703	age at menarche
EFO:0007702	hip bone mineral density
EFO:0007873	cartilage thickness measurement
EFO:0009188	Red cell distribution width
EFO:0004527	mean corpuscular hemoglobin
EFO:0004337	intelligence
EFO:0009180	rosacea severity measurement
EFO:1002040	Corneal astigmatism
EFO:0004324	body weights and measures
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007800	body fat percentage
EFO:0004995	lean body mass
EFO:0004980	appendicular lean mass
EFO:0010701	mean reticulocyte volume
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
D054079	Vascular Malformations	C14.240.850; C16.131.240.850
C585640	Activated PI3K-delta Syndrome (supp.)
C538056	Agammaglobulinemia, non-Bruton type (supp.)
C567863	Congenital Lipomatous Overgrowth, Vascular Malformations, and Epidermal Nevi (supp.)
C537327	SHORT syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL2111367 (PROTEIN COMPLEX), CHEMBL2111432 (PROTEIN COMPLEX), CHEMBL2506 (SINGLE PROTEIN), CHEMBL3038510 (PROTEIN COMPLEX), CHEMBL3559703 (PROTEIN COMPLEX GROUP), CHEMBL4296106 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

26 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 141,860 (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
CHEMBL2216870	IDELALISIB	4	10,163
CHEMBL2396661	ALPELISIB	4	6,070
CHEMBL3039502	DUVELISIB	4	5,332
CHEMBL3218576	COPANLISIB	4	4,529
CHEMBL3948730	UMBRALISIB	4	2,833
CHEMBL1879463	DACTOLISIB	3	7,988
CHEMBL2017974	BUPARLISIB	3	6,568
CHEMBL50	QUERCETIN	3	74,559
CHEMBL1236962	OMIPALISIB	2	3,989
CHEMBL2336325	VISTUSERTIB	2	1,961
CHEMBL3622533	FIMEPINOSTAT	2	2,487
CHEMBL3984425	EGANELISIB	2	1,200
CHEMBL3989870	BERZOSERTIB	2	1,265
CHEMBL4084907	BIMIRALISIB	2	1,625
CHEMBL521851	PICTILISIB	2	6,071
CHEMBL586702	ZSTK-474	2	2,827
CHEMBL3188551	GSK-2636771	2	1,814
CHEMBL4438249	AMDIZALISIB	2	14
CHEMBL4800252	RISOVALISIB	2	153
CHEMBL2216863	DEZAPELISIB	2	412
CHEMBL3683575	ROGINOLISIB	2
CHEMBL1801204	AZD-8055	1
CHEMBL3393066	VS-5584	1
CHEMBL3408248	AZD-8186	1
CHEMBL3928407	GS-9901	1
CHEMBL4439259	AZD-7648	1

Clinical evidence (CIViC)

Drug × variant × indication: 3 predictive associations from 3 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
PIK3CA Mutation OR PTEN Mutation OR PIK3R1 Mutation	Aspirin	Colorectal Cancer	Sensitivity/Response	CIViC B	EID12602
PIK3R1 Mutation	Buparlisib	Glioblastoma	Sensitivity/Response	CIViC B	EID7073
PIK3R1 Mutation	MTOR Kinase Inhibitor PP242	Breast Cancer	Sensitivity/Response	CIViC D	EID1612

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10515074	Toxicity	3	everolimus	Breast Neoplasms;Hyperglycemia;Leukopenia

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3730089	PIK3R1		0.00	0
rs10515074	PIK3R1	3	5.00	1	everolimus

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phosphatidylinositol kinases

Binding affinities (BindingDB)

1191 measured of 2768 human assays (2772 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-amino-1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-3-hydroxy-2-methylpropan-1-one	KI	0.011 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
5-[7-(3-methyl-1-methylsulfonylpyrrolidin-3-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine	KI	0.015 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
(2R)-1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-2-hydroxy-3-methylbutan-1-one	KI	0.016 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
(3R,10R,13E,16S)-10-[(4-methoxyphenyl)methyl]-3-(2-methylpropyl)-16-[(E,2R)-4-phenylbut-3-en-2-yl]-1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetrone	KI	0.016 nM	US-10112932: Benzoxazepin oxazolidinone compounds and methods of use
5-[7-[(3S)-1-(5,5-dimethyl-4H-1,3-oxazol-2-yl)-3-methylpyrrolidin-3-yl]-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine	KI	0.019 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
tert-butyl 3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylazetidine-1-carboxylate	KI	0.019 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
(2R)-2-amino-1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-2-cyclopropylethanone	KI	0.019 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
3-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-2-methyl-3-oxopropanamide	KI	0.019 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
methyl (3S)-3-[[6-(2-aminopyrimidin-5-yl)-2-morpholin-4-ylpyrimidin-4-yl]amino]-3-(hydroxymethyl)pyrrolidine-1-carboxylate	KI	0.019 nM	US-9758538: Pyrimidine derivatives
(Scheme A): Preparation of (3S)-3-{[2′-amino-5-fluoro-2-(morpholin-4-yl)-4,5′-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidin-1-ylmethanone	KI	0.02 nM	US-9758538: Pyrimidine derivatives
5-[7-(1-cyclopropylsulfonyl-3-methylazetidin-3-yl)-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydropyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine	KI	0.021 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone	KI	0.021 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-(3-hydroxyazetidin-1-yl)methanone	KI	0.021 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
2,2-difluoroethyl (3S)-3-[[6-(2-aminopyrimidin-5-yl)-2-morpholin-4-ylpyrimidin-4-yl]amino]-3-(hydroxymethyl)pyrrolidine-1-carboxylate	KI	0.021 nM	US-9758538: Pyrimidine derivatives
(2R)-2-amino-1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-2-cyclopropylethanone	KI	0.022 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
(2S)-1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-2-hydroxy-3-methylbutan-1-one	KI	0.022 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
(2R)-2-amino-1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-3-methylbutan-1-one	KI	0.022 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-(1-methylpyrazol-3-yl)methanone	KI	0.022 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
ethyl (3S)-3-[[6-(2-aminopyrimidin-5-yl)-2-morpholin-4-ylpyrimidin-4-yl]amino]-3-(hydroxymethyl)pyrrolidine-1-carboxylate	KI	0.022 nM	US-9758538: Pyrimidine derivatives
2-amino-1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-2-methylpropan-1-one	KI	0.023 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
5-[7-[(3S)-3-methyl-1-methylsulfonylpyrrolidin-3-yl]-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydropyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine	KI	0.023 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
(2S)-2-[[2-[2-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide	KI	0.023 nM	US-10112932: Benzoxazepin oxazolidinone compounds and methods of use
2-amino-1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-2-methylpropan-1-one	KI	0.024 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
5-[7-(1-ethylsulfonyl-3-methylazetidin-3-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine	KI	0.024 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
5-[7-(3-methyl-1-propan-2-ylsulfonylazetidin-3-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine	KI	0.024 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
3-amino-1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-3-methylbutan-1-one	KI	0.024 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-cyclopropylmethanone	KI	0.024 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
tert-butyl 4-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-4-methylpiperidine-1-carboxylate	KI	0.024 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-(1-methylcyclopropyl)methanone	KI	0.025 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-2-methyl-2-(methylamino)propan-1-one	KI	0.025 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
(1-methylcyclopropyl) (3S)-3-[[6-(2-aminopyrimidin-5-yl)-2-morpholin-4-ylpyrimidin-4-yl]amino]-3-(hydroxymethyl)pyrrolidine-1-carboxylate	KI	0.025 nM	US-9758538: Pyrimidine derivatives
(2R)-2-amino-1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]butan-1-one	KI	0.026 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
(2R)-2-amino-1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-3-fluoropropan-1-one	KI	0.026 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-(azetidin-3-yl)methanone	KI	0.026 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-[(2S)-pyrrolidin-2-yl]methanone	KI	0.026 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
propan-2-yl (3S)-3-[[6-(2-aminopyrimidin-5-yl)-2-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]amino]-3-(hydroxymethyl)pyrrolidine-1-carboxylate	KI	0.026 nM	US-9758538: Pyrimidine derivatives
[(3S)-3-[[6-(2-aminopyrimidin-5-yl)-2-morpholin-4-ylpyrimidin-4-yl]amino]-3-(hydroxymethyl)pyrrolidin-1-yl]-(1H-imidazol-2-yl)methanone	KI	0.026 nM	US-9758538: Pyrimidine derivatives
5-[7-[(3S)-3-methyl-1-methylsulfonylpyrrolidin-3-yl]-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine	KI	0.027 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidine-1-sulfonamide	KI	0.027 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-2-methoxyethanone	KI	0.027 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-[(3R)-oxolan-3-yl]methanone	KI	0.027 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
ethyl (3S)-3-[[4-(2-aminopyrimidin-5-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino]-3-(hydroxymethyl)pyrrolidine-1-carboxylate	KI	0.027 nM	US-9758538: Pyrimidine derivatives
2,2-difluoroethyl (3S)-3-[[4-(2-aminopyrimidin-5-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino]-3-(hydroxymethyl)pyrrolidine-1-carboxylate	KI	0.027 nM	US-9758538: Pyrimidine derivatives
1-[(3R)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-2-cyclopropyl-2-hydroxyethanone	KI	0.028 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-(3-hydroxycyclobutyl)methanone	KI	0.028 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-[(3S)-oxolan-3-yl]methanone	KI	0.028 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
(3R)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-N,3-dimethylpyrrolidine-1-sulfonamide	KI	0.029 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
tert-butyl 3-[[6-(2-aminopyrimidin-5-yl)-2-morpholin-4-ylpyrimidin-4-yl]amino]-3-(hydroxymethyl)pyrrolidine-1-carboxylate	KI	0.029 nM	US-9758538: Pyrimidine derivatives
5-[7-(1-cyclopropylsulfonylazetidin-3-yl)-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydropyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine	KI	0.03 nM	US-9260439: Dihydropyrrolopyrimidine derivatives
3-[4-(2-aminopyrimidin-5-yl)-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-N,N-dimethylazetidine-1-sulfonamide	KI	0.03 nM	US-9260439: Dihydropyrrolopyrimidine derivatives

ChEMBL bioactivities

3730 potent at pChembl≥5 of 3848 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	Ki	0.01	nM	CHEMBL4850297
11.00	Ki	0.01	nM	CHEMBL4869783
10.96	Ki	0.011	nM	CHEMBL3943270
10.90	Ki	0.01259	nM	CHEMBL4167702
10.82	Ki	0.015	nM	CHEMBL3984086
10.80	Ki	0.016	nM	CHEMBL3925423
10.80	Ki	0.01585	nM	CHEMBL4858875
10.72	Ki	0.019	nM	CHEMBL3924367
10.72	Ki	0.019	nM	CHEMBL3964422
10.72	Ki	0.019	nM	CHEMBL3917427
10.72	Ki	0.019	nM	CHEMBL3934181
10.72	IC50	0.019	nM	OMIPALISIB
10.72	Ki	0.019	nM	CHEMBL4764484
10.70	Ki	0.02	nM	CHEMBL5847613
10.68	Ki	0.021	nM	CHEMBL3933148
10.68	Ki	0.021	nM	CHEMBL3950868
10.68	Ki	0.021	nM	CHEMBL3952408
10.68	Ki	0.021	nM	CHEMBL4778025
10.66	Ki	0.022	nM	CHEMBL3958509
10.66	Ki	0.022	nM	CHEMBL3967130
10.66	Ki	0.022	nM	CHEMBL3916399
10.66	Ki	0.022	nM	CHEMBL3969015
10.66	Ki	0.022	nM	CHEMBL5808475
10.64	Ki	0.023	nM	CHEMBL3932221
10.64	Ki	0.023	nM	CHEMBL3902135
10.62	Ki	0.024	nM	CHEMBL3956275
10.62	Ki	0.024	nM	CHEMBL3907741
10.62	Ki	0.024	nM	CHEMBL3926126
10.62	Ki	0.024	nM	CHEMBL3949378
10.62	Ki	0.024	nM	CHEMBL3966977
10.62	Ki	0.024	nM	CHEMBL3980813
10.60	Ki	0.025	nM	CHEMBL3926068
10.60	Ki	0.025	nM	CHEMBL3930628
10.60	Ki	0.02512	nM	CHEMBL4873390
10.60	Ki	0.02512	nM	CHEMBL4165185
10.60	Ki	0.02512	nM	CHEMBL4175571
10.60	Ki	0.025	nM	CHEMBL6022825
10.59	Ki	0.026	nM	CHEMBL3981905
10.59	Ki	0.026	nM	CHEMBL3946605
10.59	Ki	0.026	nM	CHEMBL3935717
10.59	Ki	0.026	nM	CHEMBL3917991
10.59	Ki	0.026	nM	CHEMBL5775210
10.59	Ki	0.026	nM	CHEMBL5871963
10.57	Ki	0.027	nM	CHEMBL3908620
10.57	Ki	0.027	nM	CHEMBL3975616
10.57	Ki	0.027	nM	CHEMBL3940617
10.57	Ki	0.027	nM	CHEMBL3983948
10.57	Ki	0.027	nM	CHEMBL5920897
10.57	Ki	0.027	nM	CHEMBL5928898
10.55	Ki	0.028	nM	CHEMBL3975649

PubChem BioAssay actives

2545 with measured affinity, of 3592 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
tert-butyl (3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidine-1-carboxylate	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	<0.0001	uM
1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-2-methylpropan-1-one	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	<0.0001	uM
2-amino-1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-2-methylpropan-1-one	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	<0.0001	uM
1-[(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]-2-hydroxy-2-methylpropan-1-one	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	<0.0001	uM
5-[7-[(3S)-3-methyl-1-methylsulfonylpyrrolidin-3-yl]-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	<0.0001	uM
(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-N,3-dimethylpyrrolidine-1-sulfonamide	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	<0.0001	uM
methyl (3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidine-1-carboxylate	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	<0.0001	uM
2,2-difluoroethyl (3S)-3-[[6-(2-aminopyrimidin-5-yl)-5-fluoro-2-morpholin-4-ylpyrimidin-4-yl]amino]-3-(hydroxymethyl)pyrrolidine-1-carboxylate	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	<0.0001	uM
tert-butyl (3S)-3-[[6-(2-aminopyrimidin-5-yl)-2-morpholin-4-ylpyrimidin-4-yl]amino]-3-(hydroxymethyl)pyrrolidine-1-carboxylate	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	<0.0001	uM
methyl (3S)-3-[[6-(2-aminopyrimidin-5-yl)-2-morpholin-4-ylpyrimidin-4-yl]amino]-3-(hydroxymethyl)pyrrolidine-1-carboxylate	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	<0.0001	uM
methyl (3S)-3-[[6-(2-aminopyrimidin-5-yl)-5-fluoro-2-morpholin-4-ylpyrimidin-4-yl]amino]-3-(hydroxymethyl)pyrrolidine-1-carboxylate	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	<0.0001	uM
2,2-difluoroethyl (3S)-3-[[6-(2-aminopyrimidin-5-yl)-2-morpholin-4-ylpyrimidin-4-yl]amino]-3-(hydroxymethyl)pyrrolidine-1-carboxylate	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	<0.0001	uM
N-[2-[2-fluoro-4-[(4-propan-2-ylpiperazin-1-yl)methyl]phenyl]-4-pyridinyl]-2-methoxy-5-morpholin-4-ylpyridine-3-sulfonamide	1768974: Inhibition of recombinant human N-terminal His6-tagged full length P110delta/full length untagged human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by HTRF assay	ki	<0.0001	uM
N-[2-[4-[(4-tert-butylpiperazin-1-yl)methyl]phenyl]-4-pyridinyl]-2-methoxy-5-morpholin-4-ylpyridine-3-sulfonamide	1768974: Inhibition of recombinant human N-terminal His6-tagged full length P110delta/full length untagged human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by HTRF assay	ki	<0.0001	uM
N-[2-[4-[(4-tert-butylpiperazin-1-yl)methyl]-2-fluorophenyl]-4-pyridinyl]-2-methoxy-5-morpholin-4-ylpyridine-3-sulfonamide	1768974: Inhibition of recombinant human N-terminal His6-tagged full length P110delta/full length untagged human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by HTRF assay	ki	<0.0001	uM
2-methoxy-5-morpholin-4-yl-N-[2-[4-[(4-propan-2-ylpiperazin-1-yl)methyl]phenyl]-4-pyridinyl]pyridine-3-sulfonamide	1768974: Inhibition of recombinant human N-terminal His6-tagged full length P110delta/full length untagged human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by HTRF assay	ki	<0.0001	uM
N-[2-[4-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-2-fluorophenyl]-4-pyridinyl]-2-methoxy-5-morpholin-4-ylpyridine-3-sulfonamide	1768974: Inhibition of recombinant human N-terminal His6-tagged full length P110delta/full length untagged human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by HTRF assay	ki	<0.0001	uM
5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxy-N-[5-[4-[(4-propan-2-ylpiperazin-1-yl)methyl]phenyl]-3-pyridinyl]pyridine-3-sulfonamide	1768974: Inhibition of recombinant human N-terminal His6-tagged full length P110delta/full length untagged human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by HTRF assay	ki	<0.0001	uM
5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxy-N-[5-[4-[[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]methyl]phenyl]-3-pyridinyl]pyridine-3-sulfonamide	1768974: Inhibition of recombinant human N-terminal His6-tagged full length P110delta/full length untagged human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by HTRF assay	ki	<0.0001	uM
5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxy-N-[5-[6-[(4-propan-2-ylpiperazin-1-yl)methyl]-3-pyridinyl]-3-pyridinyl]pyridine-3-sulfonamide	1768974: Inhibition of recombinant human N-terminal His6-tagged full length P110delta/full length untagged human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by HTRF assay	ki	<0.0001	uM
5-(3,6-dihydro-2H-pyran-4-yl)-N-[5-[4-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]phenyl]-3-pyridinyl]-2-methoxypyridine-3-sulfonamide	1768974: Inhibition of recombinant human N-terminal His6-tagged full length P110delta/full length untagged human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by HTRF assay	ki	<0.0001	uM
2,4-difluoro-N-[2-methoxy-5-(4-pyridazin-4-ylquinolin-6-yl)-3-pyridinyl]benzenesulfonamide	1467657: Competitive inhibition of human PI3K p110alpha/p85alpha using PIP2 as substrate preincubated for 10 mins followed by ATP addition measured after 30 mins by HTRF assay	ic50	<0.0001	uM
1-[(3R)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl]ethanone	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	0.0001	uM
5-[7-[(3S)-1-methylsulfonylpyrrolidin-3-yl]-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	0.0001	uM
(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-N-methylpyrrolidine-1-sulfonamide	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	0.0001	uM
(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-N,3-dimethylpyrrolidine-1-carboxamide	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	0.0001	uM
2-amino-4-[[(1S)-1-(5-chloro-4-oxo-3-phenylquinazolin-2-yl)ethyl]amino]-6-methylpyrimidine-5-carbonitrile	1299722: Inhibition human full length PI3Kdelta catalytic subunit/p85alpha assessed as formation of PIP3 after 30 mins by europium labeled GRP-based TR-FRET assay	ic50	0.0001	uM
1-[(3S)-3-[[6-(2-aminopyrimidin-5-yl)-2-morpholin-4-ylpyrimidin-4-yl]amino]-3-(hydroxymethyl)pyrrolidin-1-yl]-2-methylpropan-1-one	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	0.0001	uM
tert-butyl (3S)-3-[[6-(2-aminopyrimidin-5-yl)-2-morpholin-4-ylpyrimidin-4-yl]amino]-3-methylpyrrolidine-1-carboxylate	1707451: Inhibition of recombinant human full-length PI3K p110alpha/p85alpha (322 to 600) expressed in baculovirus infected Sf21 cells using phosphatidylinositol 4,5-bisphosphate as substrate preincubated for 15 mins followed by addition of ATP and measured after 30 mins by fluorescence polarisation assay	ki	0.0001	uM
2-[(1S)-1-[(6-amino-5-ethynylpyrimidin-4-yl)amino]ethyl]-5-chloro-3-phenylquinazolin-4-one	1299722: Inhibition human full length PI3Kdelta catalytic subunit/p85alpha assessed as formation of PIP3 after 30 mins by europium labeled GRP-based TR-FRET assay	ic50	0.0001	uM
N-[2-[3-fluoro-4-[(4-propan-2-ylpiperazin-1-yl)methyl]phenyl]-4-pyridinyl]-2-methoxy-5-morpholin-4-ylpyridine-3-sulfonamide	1768974: Inhibition of recombinant human N-terminal His6-tagged full length P110delta/full length untagged human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by HTRF assay	ki	0.0001	uM
N-[2-[2-fluoro-4-[[4-(2-hydroxypropan-2-yl)piperidin-1-yl]methyl]phenyl]-4-pyridinyl]-2-methoxy-5-morpholin-4-ylpyridine-3-sulfonamide	1768974: Inhibition of recombinant human N-terminal His6-tagged full length P110delta/full length untagged human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by HTRF assay	ki	0.0001	uM
N-[2-[2,3-difluoro-4-[(4-propan-2-ylpiperazin-1-yl)methyl]phenyl]-4-pyridinyl]-2-methoxy-5-morpholin-4-ylpyridine-3-sulfonamide	1768974: Inhibition of recombinant human N-terminal His6-tagged full length P110delta/full length untagged human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by HTRF assay	ki	0.0001	uM
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro-1H-imidazo[1,2-c]quinazolin-5-ylidene]pyrimidine-5-carboxamide	1560707: Inhibition of recombinant human full-length N-terminal His-tagged p110alpha/p85alpha expressed in baculovirus expression system using PIP2 as substrate measured after 1 hr by kinase-glo assay	ic50	0.0001	uM
2-methoxy-5-morpholin-4-yl-N-[5-[4-[(4-propan-2-ylpiperazin-1-yl)methyl]phenyl]-3-pyridinyl]pyridine-3-sulfonamide	1768974: Inhibition of recombinant human N-terminal His6-tagged full length P110delta/full length untagged human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by HTRF assay	ki	0.0001	uM
2-[(S)-cyclopropyl-(7H-purin-6-ylamino)methyl]-5-methyl-3-phenylquinazolin-4-one	1777368: Inhibition of recombinant human full length His-tagged p110delta/p85alpha expressed in baculovirus expression system measured after 60 mins in presence of ATP by ATP-competitive binding assay	ic50	0.0001	uM
5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxy-N-[5-[4-(piperazin-1-ylmethyl)phenyl]-3-pyridinyl]pyridine-3-sulfonamide	1768974: Inhibition of recombinant human N-terminal His6-tagged full length P110delta/full length untagged human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by HTRF assay	ki	0.0001	uM
25-methoxy-31-methyl-22,22-dioxo-3,22lambda6,30-trithia-6,8,15,23,26-pentazahexacyclo[22.3.1.12,5.110,13.117,21.04,9]hentriaconta-1(28),2(31),4,6,8,10,12,17(29),18,20,24,26-dodecaen-16-one	1785807: Inhibition of human PI3K p110delta/p85alpha by HTRF assay	ki	0.0001	uM
18-fluoro-25-methoxy-31-methyl-22,22-dioxo-3,22lambda6,30-trithia-6,8,15,23,26-pentazahexacyclo[22.3.1.12,5.110,13.117,21.04,9]hentriaconta-1(28),2(31),4,6,8,10,12,17,19,21(29),24,26-dodecaen-16-one	1785807: Inhibition of human PI3K p110delta/p85alpha by HTRF assay	ki	0.0001	uM
5-methoxy-8,8-dioxo-8lambda6-thia-4,7,15,19,24,29-hexazahexacyclo[20.5.2.12,6.19,13.117,21.025,29]dotriaconta-1(28),2(32),3,5,9,11,13(31),17(30),18,20,22,24,26-tridecaen-14-one	1761293: Inhibition of human p110delta/p85alpha using PIP2 as substrate in presence of ATP measured by HTRF assay	ki	0.0001	uM
2,4-diamino-6-[[(1S)-1-(5-chloro-4-oxo-3-phenylquinazolin-2-yl)ethyl]amino]pyrimidine-5-carbonitrile	1299722: Inhibition human full length PI3Kdelta catalytic subunit/p85alpha assessed as formation of PIP3 after 30 mins by europium labeled GRP-based TR-FRET assay	ic50	0.0001	uM
2,4-diamino-6-[[(1S)-1-[5-chloro-3-(3-fluorophenyl)-4-oxoquinazolin-2-yl]ethyl]amino]pyrimidine-5-carbonitrile	1299722: Inhibition human full length PI3Kdelta catalytic subunit/p85alpha assessed as formation of PIP3 after 30 mins by europium labeled GRP-based TR-FRET assay	ic50	0.0001	uM
2,4-diamino-6-[[(1S)-1-[5-chloro-4-oxo-3-(1H-pyrazol-5-yl)quinazolin-2-yl]ethyl]amino]pyrimidine-5-carbonitrile	1438035: Inhibition of human full length PI3K p110delta/p85 alpha using PIP2/ATP as substrate after 30 mins by TR-FRET assay	ic50	0.0002	uM
1-[4-(4-morpholin-4-ylpyrido[3,2-d]pyrimidin-2-yl)phenyl]-3-(4-sulfamoylphenyl)urea	1467657: Competitive inhibition of human PI3K p110alpha/p85alpha using PIP2 as substrate preincubated for 10 mins followed by ATP addition measured after 30 mins by HTRF assay	ic50	0.0002	uM
2,4-difluoro-N-[2-methoxy-5-[3-[5-[2-(4-methylpiperazin-1-yl)ethyl]-1,3,4-oxadiazol-2-yl]imidazo[1,2-a]pyridin-6-yl]-3-pyridinyl]benzenesulfonamide	1560707: Inhibition of recombinant human full-length N-terminal His-tagged p110alpha/p85alpha expressed in baculovirus expression system using PIP2 as substrate measured after 1 hr by kinase-glo assay	ic50	0.0002	uM
2,4-difluoro-N-[2-methoxy-5-[3-(5-methyl-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl]-3-pyridinyl]benzenesulfonamide	1560707: Inhibition of recombinant human full-length N-terminal His-tagged p110alpha/p85alpha expressed in baculovirus expression system using PIP2 as substrate measured after 1 hr by kinase-glo assay	ic50	0.0002	uM
4-chloro-2-fluoro-N-[2-methoxy-5-[3-[5-[2-(4-methylpiperazin-1-yl)ethyl]-1,3,4-oxadiazol-2-yl]imidazo[1,2-a]pyridin-6-yl]-3-pyridinyl]benzenesulfonamide	1560707: Inhibition of recombinant human full-length N-terminal His-tagged p110alpha/p85alpha expressed in baculovirus expression system using PIP2 as substrate measured after 1 hr by kinase-glo assay	ic50	0.0002	uM
methyl 2-[4-[[[6-[5-[(2,4-difluorophenyl)sulfonylamino]-6-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-carbonyl]amino]methyl]triazol-1-yl]benzoate	1560707: Inhibition of recombinant human full-length N-terminal His-tagged p110alpha/p85alpha expressed in baculovirus expression system using PIP2 as substrate measured after 1 hr by kinase-glo assay	ic50	0.0002	uM
2,4-difluoro-N-[2-methoxy-5-[3-[5-(2-methoxyethyl)-1,3,4-oxadiazol-2-yl]imidazo[1,2-a]pyridin-6-yl]-3-pyridinyl]benzenesulfonamide	1560707: Inhibition of recombinant human full-length N-terminal His-tagged p110alpha/p85alpha expressed in baculovirus expression system using PIP2 as substrate measured after 1 hr by kinase-glo assay	ic50	0.0002	uM
3-[5-[6-[5-[(2,4-difluorophenyl)sulfonylamino]-6-methoxy-3-pyridinyl]imidazo[1,2-a]pyridin-3-yl]-1,3,4-oxadiazol-2-yl]benzoic acid	1560707: Inhibition of recombinant human full-length N-terminal His-tagged p110alpha/p85alpha expressed in baculovirus expression system using PIP2 as substrate measured after 1 hr by kinase-glo assay	ic50	0.0002	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases methylation, increases phosphorylation, affects cotreatment, decreases phosphorylation, decreases reaction (+3 more)	6
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases phosphorylation, decreases expression	4
Cyclosporine	decreases expression, affects cotreatment	4
(+)-JQ1 compound	decreases expression, increases expression	3
Acetylcysteine	decreases phosphorylation, decreases reaction, increases abundance, increases reaction, increases expression	3
Dexamethasone	increases expression, affects cotreatment	3
Oxygen	decreases expression, increases expression, increases reaction, affects cotreatment, decreases phosphorylation (+1 more)	3
Tetrachlorodibenzodioxin	decreases expression, increases expression, affects expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
mono-(2-ethylhexyl)phthalate	increases expression, increases reaction, decreases phosphorylation	2
bisphenol A diglycidyl ether	decreases reaction, increases phosphorylation, decreases phosphorylation	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases reaction, increases phosphorylation, affects cotreatment, decreases expression	2
Resveratrol	affects binding, decreases activity, decreases reaction, increases expression	2
Wortmannin	decreases activity, affects cotreatment, decreases phosphorylation, decreases reaction	2
Endosulfan	increases phosphorylation, decreases expression, affects reaction, decreases reaction	2
Formaldehyde	decreases expression, increases expression	2
Glucose	increases reaction, decreases reaction, affects cotreatment, decreases phosphorylation, affects binding	2
Hydrogen Peroxide	decreases phosphorylation, decreases reaction, increases reaction, affects reaction	2
Tretinoin	increases expression	2
Cadmium Chloride	decreases expression	2
tert-Butylhydroperoxide	affects cotreatment, increases expression, decreases reaction, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
geldanamycin	increases expression	1
quinone	decreases expression, decreases reaction	1
2,4,6-tribromophenol	decreases expression	1
oxybenzone	increases expression	1
uranyl acetate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1

ChEMBL screening assays

493 unique, capped per target: 470 binding, 23 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1105939	Binding	Inhibition of PIK3CA/PIK3R1 at 5 uM	Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors. — Bioorg Med Chem Lett
CHEMBL4005472	ADMET	Inhibition of human full length PI3K p110alpha/p85 alpha using PIP2/ATP as substrate after 30 mins by TR-FRET assay	Discovery of a Phosphoinositide 3-Kinase (PI3K) β/δ Inhibitor for the Treatment of Phosphatase and Tensin Homolog (PTEN) Deficient Tumors: Building PI3Kβ Potency in a PI3Kδ-Selective Template by Targeting Nonconserved Asp856. — J Med Chem

Cellosaurus cell lines

158 cell lines: 154 cancer cell line, 2 transformed cell line, 1 induced pluripotent stem cell, 1 hybrid cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0028	AN3-CA	Cancer cell line	Female
CVCL_0395	LNCaP	Cancer cell line	Male
CVCL_0465	OVCAR-3	Cancer cell line	Female
CVCL_1379	LNCaP clone FGC	Cancer cell line	Male
CVCL_1859	CCRF-HSB-2	Cancer cell line	Male
CVCL_1882	ONCO-DG-1	Cancer cell line	Female
CVCL_1Y12	HSB2/GS	Cancer cell line	Male
CVCL_2529	Ishikawa	Cancer cell line	Female
CVCL_3872	LNCaP-CL1	Cancer cell line	Male
CVCL_4782	LNCaP C4-2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer