PIK3R5

Summary

PIK3R5 (phosphoinositide-3-kinase regulatory subunit 5, HGNC:30035) is a protein-coding gene on chromosome 17p13.1, encoding Phosphoinositide 3-kinase regulatory subunit 5 (Q8WYR1). Regulatory subunit of the PI3K gamma complex.

Phosphatidylinositol 3-kinases (PI3Ks) phosphorylate the inositol ring of phosphatidylinositol at the 3-prime position, and play important roles in cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. The PI3Ks are divided into three classes: I, II and III, and only the class I PI3Ks are involved in oncogenesis. This gene encodes the 101 kD regulatory subunit of the class I PI3K gamma complex, which is a dimeric enzyme, consisting of a 110 kD catalytic subunit gamma and a regulatory subunit of either 55, 87 or 101 kD. This protein recruits the catalytic subunit from the cytosol to the plasma membrane through high-affinity interaction with G-beta-gamma proteins. Multiple alternatively spliced transcript variants encoding two distinct isoforms have been found.

Source: NCBI Gene 23533 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 210 total
• Regional missense constraint (gnomAD): 1 of 6 regions constrained (≈2% of expected missense variation)
• GTEx eGene: eQTL in 10 tissues, sQTL in 3 (q < 0.05)
• Phenotypes (HPO): 37
• Drug target: yes — 26 via a complex or family; 4 molecules with ChEMBL bioactivity
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.44 (moderately constrained)
• MANE Select transcript: NM_001142633
• Notable: 210 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30035
Approved symbol	PIK3R5
Name	phosphoinositide-3-kinase regulatory subunit 5
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	P101-PI3K, p101
Ensembl gene	ENSG00000141506
Ensembl biotype	protein_coding
OMIM	611317
Entrez	23533

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 10 protein_coding, 6 protein_coding_CDS_not_defined, 4 retained_intron, 1 nonsense_mediated_decay

MANE Select: ENST00000447110

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 2, TSL 3: 6, TSL 4: 1, TSL 5: 6

ENST00000447110, ENST00000269300, ENST00000577214, ENST00000577981, ENST00000578457, ENST00000578515, ENST00000578743, ENST00000580959, ENST00000581552, ENST00000581895, ENST00000583039, ENST00000583222, ENST00000583810, ENST00000584456, ENST00000584803, ENST00000585260, ENST00000611902, ENST00000616147, ENST00000623421, ENST00000935159, ENST00001137438

RefSeq mRNA: 11 — MANE Select: NM_001142633 NM_001142633, NM_001251851, NM_001251852, NM_001251853, NM_001251855, NM_001388396, NM_001388397, NM_001388398, NM_001388399, NM_001388400, NM_014308

CCDS: CCDS11147, CCDS73986, CCDS92257

Canonical transcript exons

ENST00000447110 — 19 exons

Exon	Start	End
ENSE00001732883	8965596	8965707
ENSE00003475774	8904777	8904915
ENSE00003480734	8887096	8887221
ENSE00003497637	8888171	8888891
ENSE00003499805	8886477	8886605
ENSE00003523453	8889973	8890126
ENSE00003540632	8889139	8889222
ENSE00003544890	8881630	8881712
ENSE00003545380	8881788	8881881
ENSE00003559638	8890738	8890912
ENSE00003582925	8893586	8893655
ENSE00003609406	8886229	8886322
ENSE00003611364	8909074	8909174
ENSE00003626439	8880905	8881017
ENSE00003653688	8884707	8884783
ENSE00003675014	8887521	8887683
ENSE00003683111	8911392	8911507
ENSE00003687716	8905669	8905737
ENSE00003735902	8878916	8880786

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 97.91.

FANTOM5 (CAGE): breadth broad, TPM avg 21.2863 / max 1472.0347, expressed in 618 samples.

Highest expression (Bgee): granulocyte, blood, monocyte, leukocyte, mononuclear cell.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PIK3R5 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 10 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

13 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	5.0e-39	-0.53	17:8890588:T:C
Whole Blood	eqtl	1.0e-12	-0.17	17:8882698:C:G
Whole Blood	sqtl	1.6e-07	-0.50	17:8887758:T:C
Nerve Tibial	eqtl	2.9e-04	-0.14	17:8884530:G:C
Brain Cerebellum	eqtl	7.5e-03	-0.43	17:9821161:G:A
Artery Tibial	sqtl	1.0e-02	+1.12	17:8934436:T:C
Prostate	eqtl	1.3e-02	+0.70	17:9798718:G:C
Lung	eqtl	2.0e-02	-0.14	17:8882698:C:G
Testis	sqtl	2.1e-02	+0.37	17:8881770:A:C
Colon Sigmoid	eqtl	2.4e-02	-0.51	17:9937025:A:G
Brain Frontal Cortex BA9	eqtl	3.0e-02	-0.46	17:9425792:C:A
Skin Sun Exposed Lower leg	eqtl	4.2e-02	-0.11	17:9935429:C:T
Brain Caudate basal ganglia	eqtl	4.6e-02	-0.47	17:9605944:T:C

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
164489	20.9447	614
164491	0.1609	77
164490	0.1286	68
164459	0.0471	21
164460	0.0049	1

Top tissues by expression

showing 100 of 276 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.91	gold quality
blood	UBERON:0000178	96.12	gold quality
monocyte	CL:0000576	95.10	gold quality
leukocyte	CL:0000738	94.92	gold quality
mononuclear cell	CL:0000842	94.79	gold quality
spleen	UBERON:0002106	90.80	gold quality
bone marrow cell	CL:0002092	88.50	gold quality
upper lobe of left lung	UBERON:0008952	88.19	gold quality
bone marrow	UBERON:0002371	87.39	gold quality
upper lobe of lung	UBERON:0008948	87.17	gold quality
lymph node	UBERON:0000029	86.51	gold quality
right lung	UBERON:0002167	86.04	gold quality
vermiform appendix	UBERON:0001154	85.92	gold quality
caecum	UBERON:0001153	82.37	gold quality
small intestine Peyer’s patch	UBERON:0003454	82.23	gold quality
gall bladder	UBERON:0002110	81.86	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.30	gold quality
right adrenal gland cortex	UBERON:0035827	79.88	gold quality
omental fat pad	UBERON:0010414	79.86	gold quality
peritoneum	UBERON:0002358	79.82	gold quality
trabecular bone tissue	UBERON:0002483	79.76	gold quality
small intestine	UBERON:0002108	79.57	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.21	gold quality
right adrenal gland	UBERON:0001233	78.44	gold quality
left adrenal gland	UBERON:0001234	78.38	gold quality
right coronary artery	UBERON:0001625	78.11	gold quality
lung	UBERON:0002048	77.99	gold quality
left adrenal gland cortex	UBERON:0035825	77.81	gold quality
left uterine tube	UBERON:0001303	77.69	gold quality
adrenal cortex	UBERON:0001235	77.53	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.50	gold quality
subcutaneous adipose tissue	UBERON:0002190	77.48	gold quality
layer of synovial tissue	UBERON:0007616	76.95	gold quality
sural nerve	UBERON:0015488	76.93	gold quality
adrenal gland	UBERON:0002369	76.07	gold quality
colonic epithelium	UBERON:0000397	75.97	gold quality
descending thoracic aorta	UBERON:0002345	75.81	gold quality
left coronary artery	UBERON:0001626	75.46	gold quality
thoracic aorta	UBERON:0001515	75.43	gold quality
transverse colon	UBERON:0001157	75.14	gold quality
ascending aorta	UBERON:0001496	75.13	gold quality
coronary artery	UBERON:0001621	75.12	gold quality
adipose tissue	UBERON:0001013	75.10	gold quality
rectum	UBERON:0001052	74.75	gold quality
tonsil	UBERON:0002372	74.62	gold quality
connective tissue	UBERON:0002384	74.58	gold quality
smooth muscle tissue	UBERON:0001135	74.28	gold quality
tibial nerve	UBERON:0001323	74.17	gold quality
mucosa of stomach	UBERON:0001199	73.99	gold quality
intestine	UBERON:0000160	73.24	gold quality
mucosa of transverse colon	UBERON:0004991	73.05	gold quality
apex of heart	UBERON:0002098	72.86	gold quality
synovial joint	UBERON:0002217	72.80	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	72.75	gold quality
sperm	CL:0000019	72.74	silver quality
right lobe of liver	UBERON:0001114	72.34	gold quality
male germ cell	CL:0000015	72.28	silver quality
minor salivary gland	UBERON:0001830	72.07	gold quality
colon	UBERON:0001155	71.99	gold quality
spinal cord	UBERON:0002240	71.89	gold quality
tongue squamous epithelium	UBERON:0006919	71.82	gold quality
ileal mucosa	UBERON:0000331	71.77	silver quality
large intestine	UBERON:0000059	71.67	gold quality
body of stomach	UBERON:0001161	71.59	gold quality
lower lobe of lung	UBERON:0008949	71.59	silver quality
right atrium auricular region	UBERON:0006631	71.29	gold quality
urinary bladder	UBERON:0001255	71.28	gold quality
muscle layer of sigmoid colon	UBERON:0035805	71.25	gold quality
thymus	UBERON:0002370	71.13	silver quality
aorta	UBERON:0000947	71.06	gold quality
mucosa of urinary bladder	UBERON:0001259	71.02	gold quality
lower esophagus muscularis layer	UBERON:0035833	70.85	gold quality
lower esophagus	UBERON:0013473	70.82	gold quality
right testis	UBERON:0004534	70.70	gold quality
mouth mucosa	UBERON:0003729	70.57	gold quality
saliva-secreting gland	UBERON:0001044	70.31	gold quality
stomach	UBERON:0000945	70.11	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	70.05	gold quality
left testis	UBERON:0004533	69.92	gold quality
cardiac atrium	UBERON:0002081	69.87	gold quality
amniotic fluid	UBERON:0000173	69.68	gold quality
visceral pleura	UBERON:0002401	69.61	gold quality
esophagus	UBERON:0001043	69.56	gold quality
anatomical system	UBERON:0000467	69.34	gold quality
multicellular organism	UBERON:0000468	69.27	gold quality
material anatomical entity	UBERON:0000465	69.26	gold quality
pleura	UBERON:0000977	69.16	silver quality
pericardium	UBERON:0002407	69.12	gold quality
heart left ventricle	UBERON:0002084	69.08	gold quality
heart	UBERON:0000948	68.80	gold quality
cardiac ventricle	UBERON:0002082	68.75	gold quality
testis	UBERON:0000473	68.63	gold quality
liver	UBERON:0002107	68.47	gold quality
esophagus mucosa	UBERON:0002469	68.39	gold quality
endocervix	UBERON:0000458	68.08	gold quality
epithelial cell of pancreas	CL:0000083	68.06	gold quality
parietal pleura	UBERON:0002400	67.99	silver quality
nasal cavity epithelium	UBERON:0005384	67.96	gold quality
olfactory bulb	UBERON:0002264	67.94	gold quality
tibial artery	UBERON:0007610	67.88	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	6.51
E-MTAB-5061	no	3.86
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 77 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	84.2	low
Spleen	tissue	20.1	not detected
Appendix	tissue	18.8	medium
Lymph node	tissue	13.3	not detected
Thymus	tissue	11.9
Basal ganglia	tissue	11.4	not detected
Putamen	tissue	11.0
Hypothalamus	tissue	9.0
Tonsil	tissue	9.0	not detected
Lung	tissue	8.6	medium
Septum	tissue	8.4
Ventral forebrain	tissue	8.2
Substantia nigra	tissue	7.7
Periaqueductal gray	tissue	7.6
Spinal cord	tissue	7.4
Medulla oblongata	tissue	7.1
Pons	tissue	7.0
Thalamus	tissue	7.0
Midbrain	tissue	6.6
Urinary bladder	tissue	6.5	not detected
Adipose tissue	tissue	6.3	not detected
Gallbladder	tissue	6.2	medium
Corpus callosum	tissue	6.1
Hippocampal formation	tissue	6.0
Amygdala	tissue	5.7
Choroid plexus	tissue	5.3
Superior colliculi	tissue	5.1
Locus coeruleus	tissue	4.9
Hippocampus	tissue	4.6	not detected
Small intestine	tissue	4.4	medium
Cerebral cortex	tissue	3.7	not detected
Smooth muscle	tissue	3.7	not detected
Adrenal gland	tissue	3.7	medium
Insular cortex	tissue	3.7
Stomach 1	tissue	3.4	medium
Prefrontal cortex	tissue	3.3
Motor cortex	tissue	3.2
Temporal cortex	tissue	3.2
Duodenum	tissue	3.1	medium
Placenta	tissue	2.9	low
Entorhinal cortex	tissue	2.9
Olfactory bulb	tissue	2.9
Retrosplenial cortex	tissue	2.9
Colon	tissue	2.7	medium
Liver	tissue	2.7	not detected
Retrosplenial and cingulate cortex	tissue	2.7
Nucleus accumbens	tissue	2.5
Esophagus	tissue	2.4	not detected
Rectum	tissue	2.4	medium
Somatosensory cortex	tissue	2.3
Cervix	tissue	2.2	medium
Testis	tissue	2.0	not detected
Occipital cortex	tissue	1.9
Breast	tissue	1.7	not detected
Salivary gland	tissue	1.6	low
Frontal cortex	tissue	1.4
Vagina	tissue	1.3	not detected
Fallopian tube	tissue	1.3	low
Caudate putamen	tissue	1.3
Skin 1	tissue	1.2	not detected

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Anterior thalamic nucleus, ventral (18.3), Area parastriata, superior (17.9), Lateral funiculus (white matter) (13.4), Nucleus rhomboideus (12.8), Nucleus gracilis (10.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

Targeting PIK3R5 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 70 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-1273H-3P	99.29	67.55	980
HSA-MIR-6809-5P	99.13	68.45	1223

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.442, missense Z 3.08 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000447110 splits into 6 regions with different missense tolerance; 1 is missense-constrained (≈2% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
17:8,880,642–8,880,976	91 / 90.5	1.01	no
17:8,880,977–8,887,525	173 / 274.1	0.63	no
17:8,887,526–8,888,730	319 / 339.8	0.94	no
17:8,888,731–8,893,606	161 / 249.5	0.65	no
17:8,893,607–8,904,780	1 / 20.6	0.05	yes (p 1.6e-05)
17:8,904,781–8,911,494	108 / 170.1	0.63	no

Literature-anchored findings (GeneRIF, showing 11)

• p101 has a role in membrane recruitment and activation of PI3K gamma (PMID:12507995)
• analysis of functional domains in the p101 regulatory subunit of phosphoinositide 3-kinase gamma (PMID:15611065)
• Overexpression of p101 activates PI3Kgamma signaling and is associated with T-cell lymphomas (PMID:17486067)
• Our characterization of the PIK3R5 protein and findings suggest that it may play a role in the development of the cerebellum and vermis. (PMID:22065524)
• expression and activities of PI3Kgamma are modified differently by p87 and p101 in vitro and in living cells, arguing for specific regulatory roles of the non-catalytic subunits in the differentiation of PI3Kgamma signaling pathways. (PMID:24014027)
• PIK3R5 promoter hypermethylation is associated with oral squamous cell carcinoma. (PMID:25374236)
• data argue for differential regulatory functions of the non-catalytic subunits and a specific Gbetagamma-dependent regulation of p101 in PI3Kgamma activation. (PMID:26173259)
• G protein betagamma translocation to the Golgi apparatus activates MAPK via p110gamma-p101 heterodimers. (PMID:33493514)
• HCP5, as the sponge of miR-1291, facilitates AML cell proliferation and restrains apoptosis via increasing PIK3R5 expression. (PMID:34187569)
• PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors. (PMID:34775477)
• Targetable leukaemia dependency on noncanonical PI3Kgamma signalling. (PMID:38720074)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pik3r5	ENSDARG00000102762
mus_musculus	Pik3r5	ENSMUSG00000020901
rattus_norvegicus	Pik3r5	ENSRNOG00000023428

Paralogs (1): PIK3R6 (ENSG00000276231)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2443588) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 3 distinct phenotype terms.

Mouse phenotype (MP)	Records
impaired neutrophil chemotaxis	2
increased neutrophil cell number	1
impaired neutrophil recruitment	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Sus scrofa	O02696	89.3%	Diamond
Gallus gallus	Q5ZIB8	61.0%	Diamond
Xenopus laevis	Q6INI0	52.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
NTN1	protein-coding	9423
PIK3R5-DT	ncRNA	101928235
STX8	protein-coding	9482
PIK3R6	protein-coding	146850
MFSD6L	protein-coding	162387
CFAP52	protein-coding	146845

Protein

Protein identifiers

Phosphoinositide 3-kinase regulatory subunit 5 — Q8WYR1 (reviewed: Q8WYR1)

Alternative names: PI3-kinase p101 subunit, Phosphatidylinositol 4,5-bisphosphate 3-kinase regulatory subunit, Protein FOAP-2, PtdIns-3-kinase p101, p101-PI3K

All UniProt accessions (6): Q8WYR1, J3KRE9, J3KSW1, J3KT66, L7RT34, X6R3K3

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory subunit of the PI3K gamma complex. Required for recruitment of the catalytic subunit to the plasma membrane via interaction with beta-gamma G protein dimers. Required for G protein-mediated activation of PIK3CG.

Subunit / interactions. Heterodimer of a catalytic subunit (PIK3CG/p120) and a regulatory (PIK3R5a/p101) subunit. Interacts with beta-gamma G protein dimers.

Subcellular location. Nucleus. Cytoplasm. Cell membrane.

Tissue specificity. Ubiquitously expressed with high expression in fetal brain compared to adult brain. Abundant expression is observed in cerebellum, cerebral cortex, cerebral meninges, and vermis cerebelli.

Disease relevance. Ataxia-oculomotor apraxia 3 (AOA3) [MIM:615217] An autosomal recessive disease characterized by cerebellar ataxia, oculomotor apraxia, areflexia and peripheral neuropathy. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Greatly activated by G gamma proteins.

Domain organisation. The heterodimerization region allows the binding to the catalytic subunit.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8WYR1-1	1	yes
Q8WYR1-2	2

RefSeq proteins (11): NP_001136105, NP_001238780, NP_001238781, NP_001238782, NP_001238784, NP_001375325, NP_001375326, NP_001375327, NP_001375328, NP_001375329, NP_055123 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019522	PIK3R5/6	Family

Pfam: PF10486

UniProt features (23 total): sequence conflict 8, region of interest 6, modified residue 3, sequence variant 2, compositionally biased region 2, chain 1, splice variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WYR1-F1	71.39	0.47

Human Protein Atlas

Protein class: Metabolic proteins, Predicted intracellular proteins, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; centriolar satellite

Antibody reliability (HPA): IH uncertain · IF supported

Functional residue map

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

Post-translational modifications (3)

Type	Positions
Phosphoserine	458, 507
N-acetylmethionine	1

Function

Pathways and Gene Ontology

Reactome pathways

8 curated (TAS) of 29; 4 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

29 pathways:

ID	Pathway	Evidence
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer ⚕	curated
R-HSA-389357	CD28 dependent PI3K/Akt signaling	curated
R-HSA-9927354	Co-stimulation by ICOS	curated
R-HSA-392451	G beta:gamma signalling through PI3Kgamma	curated
R-HSA-114604	GPVI-mediated activation cascade	curated
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	curated
R-HSA-1257604	PIP3 activates AKT signaling	curated
R-HSA-1660499	Synthesis of PIPs at the plasma membrane	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers ⚕	—
R-HSA-2219528	PI3K/AKT Signaling in Cancer ⚕	—
R-HSA-1280218	Adaptive Immune System	—
R-HSA-389356	Co-stimulation by CD28	—
R-HSA-9027276	Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	electronic
R-HSA-397795	G-protein beta:gamma signalling	—
R-HSA-388396	GPCR downstream signalling	—
R-HSA-109582	Hemostasis	—
R-HSA-168256	Immune System	—
R-HSA-9006925	Intracellular signaling by second messengers	—
R-HSA-1430728	Metabolism	—
R-HSA-556833	Metabolism of lipids	—
R-HSA-199418	Negative regulation of the PI3K/AKT network	—
R-HSA-1483255	PI Metabolism	—
R-HSA-1483257	Phospholipid metabolism	—
R-HSA-76002	Platelet activation, signaling and aggregation	—
R-HSA-388841	Regulation of T cell activation by CD28 family	—
R-HSA-162582	Signal Transduction	—
R-HSA-9006335	Signaling by Erythropoietin	—
R-HSA-372790	Signaling by GPCR	—

MSigDB gene sets: 371 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, REACTOME_CO_STIMULATION_BY_CD28, GOCC_MICROTUBULE_ORGANIZING_CENTER, EFC_Q6, KEGG_FC_EPSILON_RI_SIGNALING_PATHWAY, GOBP_GLYCEROLIPID_METABOLIC_PROCESS

GO Biological Process (6): immune response (GO:0006955), G protein-coupled receptor signaling pathway (GO:0007186), positive regulation of MAP kinase activity (GO:0043406), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), phosphatidylinositol metabolic process (GO:0046488), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897)

GO Molecular Function (3): G-protein beta/gamma-subunit complex binding (GO:0031683), 1-phosphatidylinositol-3-kinase regulator activity (GO:0046935), kinase activity (GO:0016301)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), phosphatidylinositol 3-kinase complex (GO:0005942), phosphatidylinositol 3-kinase complex, class IB (GO:0005944), membrane (GO:0016020), centriolar satellite (GO:0034451)

Reactome top-level categories

15 top-level categories:

Category	Pathways
Platelet activation, signaling and aggregation	1
Intracellular signaling by second messengers	1
PI Metabolism	1
PI3K/AKT Signaling in Cancer	1
Co-stimulation by CD28	1
G-protein beta:gamma signalling	1
Negative regulation of the PI3K/AKT network	1
Signaling by Erythropoietin	1
Regulation of T cell activation by CD28 family	1
Immune System	1
Phospholipid metabolism	1
Metabolism of lipids	1
PIP3 activates AKT signaling	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Signal Transduction	1

GO top-level categories

28 GO namespaces:

Category	Terms
cellular anatomical structure	4
immune system process	1
response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
MAP kinase activity	1
regulation of MAP kinase activity	1
positive regulation of MAPK cascade	1
positive regulation of protein serine/threonine kinase activity	1
intracellular signaling cassette	1
glycerophospholipid metabolic process	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
protein-containing complex binding	1
1-phosphatidylinositol-3-kinase activity	1
kinase regulator activity	1
transferase activity, transferring phosphorus-containing groups	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
extrinsic component of membrane	1
transferase complex, transferring phosphorus-containing groups	1
membrane protein complex	1
phosphatidylinositol 3-kinase complex, class I	1
centrosome	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 17 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
G protein-coupled receptor signaling pathway	BP	experiment
centriolar satellite	CC	direct assay
cytosol	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 1,142 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIK3R5	PIK3CG	P48736	790
PIK3R5	GNG2	P59768	753
PIK3R5	SUCLG2	Q96I99	752
PIK3R5	GNB1	P04697	726
PIK3R5	PIK3R3	Q92569	718
PIK3R5	PIK3R2	O00459	716
PIK3R5	IMMT	Q16891	680
PIK3R5	PIK3CB	P42338	643
PIK3R5	PDE3B	Q13370	637
PIK3R5	PIK3CD	O00329	633
PIK3R5	PPP1R12C	Q9BZL4	620
PIK3R5	PIK3R1	P27986	600
PIK3R5	PIK3CA	P42336	594
PIK3R5	PIK3C2G	O75747	553
PIK3R5	PIK3C2B	O00750	522

IntAct

Human interaction partners of PIK3R5 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

7 partners by confidence:

Partner	Interaction type	MIscore	Records
CFTR	physical association	0.370	1
PIK3CG	proximity	0.270	1
ADAMTS2	physical association	0.000	1
CXCL2	physical association	0.000	1
CYP4A11	physical association	0.000	1
SDHB	physical association	0.000	1
TTR	physical association	0.000	1

BioGRID (18 interactions; top human partners by supporting records): PIK3CG (Phenotypic Enhancement; 7 records), ANK3 (Cross-Linking-MS (XL-MS)), APP (Reconstituted Complex), CFTR (PCA), FPR1 (Phenotypic Enhancement), GNB1 (Phenotypic Enhancement), GNG2 (Phenotypic Enhancement), MECP2 (Affinity Capture-MS), PARP15 (Proximity Label-MS), SDHB (Two-hybrid), SNX9 (Reconstituted Complex)

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ PIK3CG-PIK3R5 complex	2	PIK3CG, PIK3R5

Disease & clinical

Genetic variants

Variant evidence for PIK3R5: 210 ClinVar records (0 pathogenic / likely pathogenic); 1 PharmGKB clinical annotation; 5 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	122
Likely benign	31
Benign	18

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 37 predictions of 1,891):

Position(s)	Effect	Δscore	Sites
17:8881018–8881019	acceptor_loss	1.0000	6
17:8881628–8881629	donor_loss	1.0000	5
17:8881713–8881714	acceptor_loss	1.0000	5
17:8881786–8881787	donor_loss	1.0000	5
17:8886227–8886228	donor_loss	1.0000	5
17:8886323–8886324	acceptor_loss	1.0000	3
17:8886475–8886476	donor_loss	1.0000	4
17:8886613–8886614	acceptor_gain	1.0000	2
17:8886636	acceptor_gain	1.0000
17:8886650	acceptor_gain	1.0000

AlphaMissense

1,314 missense substitutions predicted likely pathogenic (of 5,678 scored), across 385 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D615	8	0.971	0.985
H15	8	0.963	0.987
D11	8	0.948	0.980
F691	8	0.942	0.991
F875	8	0.938	0.991
D820	8	0.930	0.969
D525	8	0.926	0.983
F298	8	0.923	0.972
D822	8	0.904	0.969
F522	8	0.902	0.974
F85	8	0.895	0.973
F815	8	0.884	0.985
H199	8	0.835	0.963
F556	8	0.798	0.989
W42	7	0.977	0.995
W293	7	0.965	0.995
W617	7	0.959	0.996
W115	7	0.940	0.989
E133	7	0.909	0.947
R50	7	0.905	0.983

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:611317 | disease phenotypes:

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Supportive	Autosomal recessive
ataxia with oculomotor apraxia type 3	Limited	Autosomal recessive	2

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
ataxia with oculomotor apraxia type 3	Disputed	AR

Mondo (2): ataxia with oculomotor apraxia type 3 (MONDO:0014084), spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (MONDO:0018996)

HPO phenotypes

37 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000486	Strabismus
HP:0000514	Slow saccadic eye movements
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000657	Oculomotor apraxia
HP:0001152	Saccadic smooth pursuit interruptions
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001266	Choreoathetosis
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001310	Dysmetria
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0002015	Dysphagia
HP:0002141	Gait imbalance
HP:0002174	Postural tremor
HP:0002346	Head tremor
HP:0002359	Frequent falls
HP:0002839	Urinary bladder sphincter dysfunction
HP:0002936	Distal sensory impairment
HP:0003073	Hypoalbuminemia
HP:0003124	Hypercholesterolemia
HP:0003236	Elevated circulating creatine kinase activity
HP:0003474	Somatic sensory dysfunction
HP:0003477	Peripheral axonal neuropathy
HP:0003487	Babinski sign
HP:0003621	Juvenile onset
HP:0003676	Progressive
HP:0003693	Distal amyotrophy
HP:0006254	Elevated circulating alpha-fetoprotein concentration
HP:0006855	Cerebellar vermis atrophy
HP:0007141	Sensorimotor neuropathy
HP:0007256	Abnormal pyramidal sign
HP:0025708	Early young adult onset

GWAS associations

5 associations:

Study	Trait	p-value
GCST90002382_567	Eosinophil percentage of white cells	4e-12
GCST90002381_597	Eosinophil count	4e-11
GCST010571_67	Autoimmune thyroid disease	4e-10
GCST90002394_432	Monocyte percentage of white cells	8e-10
GCST008098_3	Atypical femoral fracture in phosphonate treatment	5e-6

EFO canonical traits (from GWAS)

5 canonical traits:

EFO ID	Trait name
EFO:0009958	response to bisphosphonate
EFO:0009960	atypical femoral fracture
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C537308	Spinocerebellar ataxia, autosomal recessive 1 *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3430881 (PROTEIN COMPLEX), CHEMBL3559703 (PROTEIN COMPLEX GROUP)

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes PIK3R5 — the drug acts on the assembly or class, not necessarily on this subunit alone.

26 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
BUPARLISIB	PI3-kinase class I	8	3
DACTOLISIB	PI3-kinase class I	8	3
GEDATOLISIB	PI3-kinase class I	8	3
TASELISIB	PI3-kinase class I	8	3
APITOLISIB	PI3-kinase class I	8	2
AZD-6482	PI3-kinase class I	8	2
BGT-226	PI3-kinase class I	8	2
IZORLISIB	PI3-kinase class I	8	2
OMIPALISIB	PI3-kinase class I	8	2
PANULISIB	PI3-kinase class I	8	2
PAXALISIB	PI3-kinase class I	8	2
PF-04691502	PI3-kinase class I	8	2
PICTILISIB	PI3-kinase class I	8	2
PILARALISIB	PI3-kinase class I	8	2
RECILISIB	PI3-kinase class I	8	2
SAMOTOLISIB	PI3-kinase class I	8	2
SF-1126	PI3-kinase class I	8	2
SONOLISIB	PI3-kinase class I	8	2
VOXTALISIB	PI3-kinase class I	8	2
ZSTK-474	PI3-kinase class I	8	2
DS-7423	PI3-kinase class I	8	1
GSK-1059615	PI3-kinase class I	8	1
PUQUITINIB MESYLATE DIHYDRATE	PI3-kinase class I	8	1
PWT-33587	PI3-kinase class I	8	1
VS-5584	PI3-kinase class I	8	1
WX-037	PI3-kinase class I	8	1

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 21,596 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

4 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL2017974	BUPARLISIB	3	6,850
CHEMBL1879463	DACTOLISIB	3	8,349
CHEMBL521851	PICTILISIB	2	6,322
CHEMBL3683575	ROGINOLISIB	2	75

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

1 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs444904	Toxicity	3	sorafenib	Hypertension

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs444904	PIK3R5	3	1.50	1	sorafenib

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs444904	sorafenib	Toxicity	Allele T is associated with increased risk of Hypertension when treated with sorafenib in people with Carcinoma, Renal Cell as compared to allele C.	PMID:35484400

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phosphatidylinositol kinases

Binding affinities (BindingDB)

33 measured of 33 human assays (33 total across all organisms); most potent 33 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-ylimidazo[4,5-c]quinolin-1-yl)phenyl]propanenitrile	IC50	2 nM	US-9284315: Three-ring PI3K and/or mTOR inhibitor
(2R,3S,6Z,14S,15S,17R)-6-({3-(dimethylamino)propylamino}methylidene)-8,14-dihydroxy-3-(methoxymethyl)-2,15-dimethyl-5,9-dioxo-4-oxatetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadeca-1(10),7-dien-17-yl acetate	IC50	6.4 nM
CHEMBL4088969	IC50	6.7 nM
CHEMBL4097625	IC50	7.3 nM
6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-4-{2-[4-(trifluoromethyl)phenyl]ethyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	8.1 nM
4-[2-(4-bromophenyl)ethyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	9.9 nM
4-[(4-tert-butylphenyl)methyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	10 nM
4-[(3,4-dimethylphenyl)methyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	11 nM
4-[2-(3,5-dimethylphenyl)ethyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	11 nM
4-[2-(3-methoxyphenyl)ethyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	11 nM
4-[2-(3,5-dimethoxyphenyl)ethyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	12 nM
4-[2-(3-chlorophenyl)ethyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	18 nM
4-[2-(3,4-dichlorophenyl)ethyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	18 nM
4-[2-(2,4-dichlorophenyl)ethyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	18 nM
4-[2-(4-chlorophenyl)ethyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	20 nM
4-[2-(3,4-difluorophenyl)ethyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	20 nM
4-[2-(3-methylphenyl)ethyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	21 nM
4-[2-(4-methoxyphenyl)ethyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	28 nM
4-[(4-chlorophenyl)methyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	30 nM
4-[2-(4-methylphenyl)ethyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	37 nM
CHEMBL4555071	IC50	80 nM
4-benzyl-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	97 nM
6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-4-(2-phenylethyl)-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	103 nM
6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-4-{[4-(trifluoromethyl)phenyl]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	116 nM
4-[(4-methylphenyl)methyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	124 nM
4-[2-(4-tert-butylphenyl)ethyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	140 nM
4-[(3-oxo-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-4-yl)methyl]benzonitrile	IC50	152 nM
CHEMBL4446205	IC50	158 nM
4-[(3-methylphenyl)methyl]-6-{[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one	IC50	185 nM
(5Z)-5-[(3-hydroxy-5-methoxyphenyl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	IC50	328 nM
5-(2,6-dimorpholin-4-ylpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine	IC50	7900 nM	US-10173995: Pyridine compounds used as PI3 kinase inhibitors
2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	IC50	12400 nM
NSC221019	IC50	46100 nM

ChEMBL bioactivities

430 potent at pChembl≥5 of 440 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.22	IC50	6	nM	CHEMBL3683580
8.15	IC50	7	nM	CHEMBL3683671
7.96	IC50	11	nM	CHEMBL3612310
7.96	IC50	11	nM	CHEMBL3683555
7.89	IC50	13	nM	CHEMBL3683606
7.89	IC50	13	nM	CHEMBL3683649
7.89	IC50	13	nM	CHEMBL3683695
7.85	IC50	14	nM	CHEMBL3683596
7.85	IC50	14	nM	CHEMBL3683693
7.82	IC50	15	nM	CHEMBL3683611
7.82	IC50	15	nM	CHEMBL3683686
7.80	IC50	16	nM	CHEMBL3683556
7.80	IC50	16	nM	CHEMBL3683584
7.80	IC50	16	nM	CHEMBL3683641
7.80	IC50	16	nM	CHEMBL3683644
7.77	IC50	17	nM	CHEMBL3683594
7.75	IC50	18	nM	CHEMBL3683680
7.75	IC50	18	nM	CHEMBL3683684
7.72	IC50	19	nM	CHEMBL3683613
7.70	IC50	20	nM	CHEMBL3683667
7.70	IC50	20	nM	CHEMBL3683675
7.68	IC50	21	nM	CHEMBL3683552
7.68	IC50	21	nM	CHEMBL3683632
7.68	IC50	21	nM	CHEMBL3683681
7.66	IC50	22	nM	CHEMBL3683530
7.66	IC50	22	nM	CHEMBL3683685
7.62	IC50	24	nM	CHEMBL3683612
7.62	IC50	24	nM	CHEMBL3683617
7.60	IC50	25	nM	CHEMBL3683593
7.60	IC50	25	nM	CHEMBL3683595
7.60	IC50	25	nM	CHEMBL3683647
7.60	IC50	25	nM	CHEMBL3683661
7.60	IC50	25	nM	CHEMBL3683690
7.57	IC50	27	nM	CHEMBL3683600
7.55	IC50	28	nM	CHEMBL3683672
7.55	IC50	28	nM	CHEMBL3683674
7.54	IC50	29	nM	CHEMBL3683548
7.54	IC50	29	nM	CHEMBL3683614
7.52	IC50	30	nM	CHEMBL3683615
7.51	IC50	31	nM	CHEMBL3683656
7.50	IC50	32	nM	CHEMBL3683599
7.47	IC50	34	nM	CHEMBL3683531
7.47	IC50	34	nM	CHEMBL3683533
7.47	IC50	34	nM	CHEMBL3683556
7.47	IC50	34	nM	CHEMBL3683666
7.44	IC50	36	nM	CHEMBL3683523
7.44	IC50	36	nM	CHEMBL3683610
7.42	IC50	38	nM	CHEMBL3683551
7.42	IC50	38	nM	CHEMBL3683642
7.41	IC50	39	nM	CHEMBL3683651

PubChem BioAssay actives

38 with measured affinity, of 38 total; 37 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
6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-4-[2-[4-(trifluoromethyl)phenyl]ethyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0019	uM
4-[2-(4-bromophenyl)ethyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0023	uM
4-[(4-tert-butylphenyl)methyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0024	uM
4-[(3,4-dimethylphenyl)methyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0026	uM
4-[2-(3,5-dimethylphenyl)ethyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0027	uM
4-[2-(3-methoxyphenyl)ethyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0027	uM
4-[2-(3,5-dimethoxyphenyl)ethyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0028	uM
4-[2-(3-chlorophenyl)ethyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0043	uM
4-[2-(2,4-dichlorophenyl)ethyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0043	uM
4-[2-(3,4-dichlorophenyl)ethyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0044	uM
4-[2-(4-chlorophenyl)ethyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0048	uM
4-[2-(3,4-difluorophenyl)ethyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0048	uM
4-[2-(3-methylphenyl)ethyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0050	uM
4-[2-(4-methoxyphenyl)ethyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0066	uM
4-[(4-chlorophenyl)methyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0072	uM
[(1S,6Z,9S,9aS,10R,11aS)-6-[[3-(dimethylamino)propyl-methylamino]methylidene]-1-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-4,5,7-trioxo-1,2,3,3a,5a,9,10,11-octahydroindeno[4,5-h]isochromen-10-yl] acetate	1798030: PI3K Inhibition Assay from Article 10.1021/jm7012858: “Synthesis and structure-activity relationships of ring-opened 17-hydroxywortmannins: potent phosphoinositide 3-kinase inhibitors with improved properties and anticancer efficacy.”	ic50	0.0080	uM
4-[2-(4-methylphenyl)ethyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0088	uM
1-[2-(diethylamino)ethyl]-3-[6-[5-[(4-fluorophenyl)sulfonylamino]-6-methoxy-3-pyridinyl]-1,3-benzothiazol-2-yl]urea	1245325: Inhibition of p110gamma/PIK3R5 (unknown origin) incubated for 40 mins by luciferase based ATP depletion assay	ic50	0.0110	uM
[(1R,3R,5S,9R,18S)-18-(methoxymethyl)-1,5-dimethyl-6,11,16-trioxo-13,17-dioxapentacyclo[10.6.1.02,10.05,9.015,19]nonadeca-2(10),12(19),14-trien-3-yl] acetate	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0190	uM
4-benzyl-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0230	uM
6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-4-(2-phenylethyl)-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0245	uM
6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-4-[[4-(trifluoromethyl)phenyl]methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0275	uM
4-[(4-methylphenyl)methyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0295	uM
4-[2-(4-tert-butylphenyl)ethyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0332	uM
4-[[3-oxo-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-4-yl]methyl]benzonitrile	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0361	uM
4-[(3-methylphenyl)methyl]-6-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]-1,4-benzoxazin-3-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0437	uM
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-ylimidazo[4,5-c]quinolin-1-yl)phenyl]propanenitrile	1245325: Inhibition of p110gamma/PIK3R5 (unknown origin) incubated for 40 mins by luciferase based ATP depletion assay	ic50	0.0720	uM
(5Z)-5-[(3-hydroxy-5-methoxyphenyl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	0.0777	uM
[4-[[4-[6-amino-4-(trifluoromethyl)-3-pyridinyl]-6-morpholin-4-ylpyrimidin-2-yl]amino]phenyl]-(4-methylsulfonylpiperazin-1-yl)methanone	1628743: Inhibition of PI3K p110gamma/p101 (unknown origin) using PIP2/ATP as substrate after 1 hr by kinase glo luminescent assay	ic50	0.0800	uM
N-[5-[3-[(3S)-1-(cyclopropanecarbonyl)pyrrolidin-3-yl]-4-oxoquinazolin-6-yl]-2-methoxy-3-pyridinyl]-4-fluorobenzenesulfonamide	1433190: Inhibition of P110gamma/PIK3R5 (unknown origin) using L-alpha-phosphatidylinositol as substrate after 40 mins by ATP depletion assay	ic50	0.1160	uM
4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine	1202631: Inhibition of p110gamma/PIK3R5 (unknown origin) using L-alpha-phosphatidylinositol incubated for 40 mins by ADP depletion detection based luciferase assay	ic50	0.1170	uM
5-(2,6-dimorpholin-4-ylpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine	1628743: Inhibition of PI3K p110gamma/p101 (unknown origin) using PIP2/ATP as substrate after 1 hr by kinase glo luminescent assay	ic50	0.1290	uM
5-[2-[(4aS,7aS)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrol-6-yl]-6-morpholin-4-ylpyrimidin-4-yl]-4-(trifluoromethyl)pyridin-2-amine	1628743: Inhibition of PI3K p110gamma/p101 (unknown origin) using PIP2/ATP as substrate after 1 hr by kinase glo luminescent assay	ic50	0.1580	uM
N-[5-[3-[(3S)-1-(cyclopropylmethyl)pyrrolidin-3-yl]-4-oxoquinazolin-6-yl]-2-methoxy-3-pyridinyl]-4-fluorobenzenesulfonamide	1433190: Inhibition of P110gamma/PIK3R5 (unknown origin) using L-alpha-phosphatidylinositol as substrate after 40 mins by ATP depletion assay	ic50	0.1810	uM
3-(6,7-dimethoxy-4-morpholin-4-ylquinazolin-2-yl)-5-hydroxybenzamide	1202631: Inhibition of p110gamma/PIK3R5 (unknown origin) using L-alpha-phosphatidylinositol incubated for 40 mins by ADP depletion detection based luciferase assay	ic50	0.3940	uM
3-(6,7-dimethoxy-4-morpholin-4-ylquinazolin-2-yl)-5-(trifluoromethoxy)benzamide	1202631: Inhibition of p110gamma/PIK3R5 (unknown origin) using L-alpha-phosphatidylinositol incubated for 40 mins by ADP depletion detection based luciferase assay	ic50	0.4650	uM
2-morpholin-4-yl-8-phenylchromen-4-one	1798510: PI3Kgamma Inhibition Assay from Article 10.1016/j.bmcl.2006.10.080: “Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.”	ic50	1.7200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
Tobacco Smoke Pollution	decreases methylation, increases expression, increases methylation	3
Valproic Acid	decreases methylation, increases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Ozone	affects expression, increases abundance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
GSK-J4	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
bisphenol A	decreases methylation	1
ochratoxin A	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Fulvestrant	decreases methylation	1
Air Pollutants, Occupational	affects expression	1
Benzene	increases expression	1
Calcitriol	decreases expression	1
Copper	affects binding, increases expression	1
Methapyrilene	increases methylation	1
Methyl Methanesulfonate	decreases expression	1
Nickel	increases expression	1
Oligomycins	affects response to substance, decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3418084	Binding	Inhibition of p110gamma/PIK3R5 (unknown origin) using L-alpha-phosphatidylinositol incubated for 40 mins by ADP depletion detection based luciferase assay	Synthesis and antitumor activities evaluation of m-(4-morpholinoquinazolin-2-yl)benzamides in vitro and in vivo. — *Eur J Med Chem*

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8SV	Ubigene HCT 116 PIK3R5 KO	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

3 trials:

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04297891	Not specified	UNKNOWN	Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias
NCT07798674	Not specified	RECRUITING	TreatHSP Platform: Adaptive Natural History Platform for Ataxias, HSPs, and Spastic Ataxias

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PIK3R5 across ~30M SureChEMBL compounds — explore on Sugi Predict.