PIK3C3

Summary

PIK3C3 (phosphatidylinositol 3-kinase catalytic subunit type 3, HGNC:8974) is a protein-coding gene on chromosome 18q12.3, encoding Phosphatidylinositol 3-kinase catalytic subunit type 3 (Q8NEB9). Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of…. It is a selective cancer dependency (DepMap: 74.6% of cell lines).

Enables 1-phosphatidylinositol-3-kinase activity. Involved in several processes, including early endosome to late endosome transport; macroautophagy; and positive regulation of natural killer cell mediated cytotoxicity. Acts upstream of or within autophagy and positive regulation of protein lipidation. Located in autolysosome; late endosome; and midbody. Is active in plasma membrane.

Source: NCBI Gene 5289 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 112 total
• GTEx eGene: eQTL in 41 tissues, sQTL in 11 (q < 0.05)
• ChEMBL bioactivity: 19 clinical-phase molecules tested; no curated mechanism-of-action drug
• Cancer dependency (DepMap): dependent in 74.6% of screened cell lines
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.00 (unconstrained)
• MANE Select transcript: NM_002647
• Interaction hub: 5,436 STRING partners (top 1% of genes corpus-wide)
• Notable: 112 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8974
Approved symbol	PIK3C3
Name	phosphatidylinositol 3-kinase catalytic subunit type 3
Location	18q12.3
Locus type	gene with protein product
Status	Approved
Aliases	Vps34, hVps34
Ensembl gene	ENSG00000078142
Ensembl biotype	protein_coding
OMIM	602609
Entrez	5289

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 20 protein_coding, 11 nonsense_mediated_decay, 6 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000262039

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

ENST00000262039, ENST00000398870, ENST00000585528, ENST00000586545, ENST00000587261, ENST00000587328, ENST00000587402, ENST00000588156, ENST00000588631, ENST00000589056, ENST00000589550, ENST00000590013, ENST00000590220, ENST00000591011, ENST00000593098, ENST00000858066, ENST00000858067, ENST00000858068, ENST00000858069, ENST00000858070, ENST00000938600, ENST00000959750, ENST00000959751, ENST00001005799, ENST00001005800, ENST00001029704, ENST00001029705, ENST00001029707, ENST00001072109, ENST00001108234, ENST00001108235, ENST00001108236, ENST00001112690, ENST00001112691, ENST00001112692, ENST00001112693, ENST00001118207, ENST00001121837, ENST00001131704

RefSeq mRNA: 2 — MANE Select: NM_002647 NM_001308020, NM_002647

CCDS: CCDS11920, CCDS77180

Canonical transcript exons

ENST00000262039 — 25 exons

Exon	Start	End
ENSE00002814667	42037692	42037820
ENSE00002825386	42081123	42087830
ENSE00003529151	42064740	42064830
ENSE00003555544	42067388	42067513
ENSE00003712355	42038781	42038850
ENSE00003719715	42057883	42058051
ENSE00003723898	42043733	42043817
ENSE00003728598	42040677	42040741
ENSE00003750488	42049531	42049605
ENSE00004283020	41987812	41987898
ENSE00004283021	41995890	41995994
ENSE00004283022	42015476	42015566
ENSE00004283024	41955234	41955359
ENSE00004283025	42013442	42013596
ENSE00004283026	42029325	42029441
ENSE00004283027	41962489	41962632
ENSE00004283028	42020638	42020705
ENSE00004283029	42033826	42033957
ENSE00004283030	41996638	41996730
ENSE00004283031	41990459	41990554
ENSE00004283032	41970327	41970456
ENSE00004283033	42004356	42004541
ENSE00004283034	41993270	41993341
ENSE00004283035	41957570	41957758
ENSE00004283036	42027443	42027548

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 96.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.0171 / max 1090.8747, expressed in 1817 samples.

Highest expression (Bgee): calcaneal tendon, adrenal tissue, ventricular zone, endothelial cell, stromal cell of endometrium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PIK3C3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 41 tissues and its splicing (sQTL) in 11 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 52 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	1.8e-23	-0.25	18:42056401:C:A
Esophagus Mucosa	eqtl	2.9e-15	-0.28	18:41950846:G:A
Whole Blood	eqtl	3.5e-15	-0.16	18:41954860:C:T
Artery Tibial	sqtl	7.3e-15	-0.69	18:42040968:G:A
Nerve Tibial	sqtl	3.8e-13	+0.52	18:41993629:T:G
Cells Cultured fibroblasts	eqtl	1.9e-12	-0.21	18:41954860:C:T
Skin Sun Exposed Lower leg	eqtl	2.3e-12	-0.17	18:41951174:A:G
Thyroid	eqtl	5.0e-12	-0.18	18:41962442:GAT:G
Lung	eqtl	1.5e-11	-0.24	18:41962442:GAT:G
Esophagus Muscularis	eqtl	1.1e-10	-0.16	18:41974975:G:A
Brain Frontal Cortex BA9	eqtl	3.0e-10	-0.34	18:41951174:A:G
Brain Cerebellum	eqtl	2.2e-09	-0.27	18:41962442:GAT:G
Brain Cerebellar Hemisphere	eqtl	6.4e-09	-0.32	18:41950846:G:A
Skin Not Sun Exposed Suprapubic	eqtl	6.7e-09	-0.17	18:41974975:G:A
Artery Tibial	eqtl	8.1e-09	-0.22	18:41954860:C:T
Testis	sqtl	1.0e-08	-0.67	18:41987118:AG:A
Brain Cortex	eqtl	1.1e-08	-0.48	18:42025092:A:G
Pituitary	eqtl	2.7e-08	-0.27	18:41962442:GAT:G
Testis	eqtl	4.0e-08	-0.14	18:42110517:T:C
Adipose Subcutaneous	eqtl	5.0e-08	-0.18	18:42057104:G:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
170003	34.4736	1817
170004	0.5435	257

Top tissues by expression

showing 100 of 298 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	96.86	gold quality
adrenal tissue	UBERON:0018303	96.14	gold quality
ventricular zone	UBERON:0003053	95.23	gold quality
endothelial cell	CL:0000115	94.73	gold quality
stromal cell of endometrium	CL:0002255	94.55	gold quality
ganglionic eminence	UBERON:0004023	93.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.70	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.57	gold quality
right adrenal gland cortex	UBERON:0035827	92.26	gold quality
right testis	UBERON:0004534	92.12	gold quality
left testis	UBERON:0004533	91.97	gold quality
right adrenal gland	UBERON:0001233	91.84	gold quality
testis	UBERON:0000473	91.56	gold quality
nerve	UBERON:0001021	91.45	gold quality
tibial nerve	UBERON:0001323	91.45	gold quality
Brodmann (1909) area 23	UBERON:0013554	91.45	gold quality
skin of leg	UBERON:0001511	91.39	gold quality
postcentral gyrus	UBERON:0002581	91.14	gold quality
adrenal gland	UBERON:0002369	91.12	gold quality
monocyte	CL:0000576	91.10	gold quality
tonsil	UBERON:0002372	91.07	gold quality
corpus callosum	UBERON:0002336	91.04	gold quality
popliteal artery	UBERON:0002250	91.01	gold quality
tibial artery	UBERON:0007610	91.01	gold quality
left adrenal gland	UBERON:0001234	91.00	gold quality
left ovary	UBERON:0002119	90.99	gold quality
tendon	UBERON:0000043	90.95	gold quality
mucosa of transverse colon	UBERON:0004991	90.95	gold quality
leukocyte	CL:0000738	90.94	gold quality
skin of abdomen	UBERON:0001416	90.90	gold quality
metanephros cortex	UBERON:0010533	90.89	gold quality
left adrenal gland cortex	UBERON:0035825	90.82	gold quality
right lung	UBERON:0002167	90.79	gold quality
mononuclear cell	CL:0000842	90.78	gold quality
adenohypophysis	UBERON:0002196	90.71	gold quality
colonic epithelium	UBERON:0000397	90.66	gold quality
adrenal cortex	UBERON:0001235	90.60	gold quality
omental fat pad	UBERON:0010414	90.60	gold quality
aorta	UBERON:0000947	90.58	gold quality
embryo	UBERON:0000922	90.57	gold quality
peritoneum	UBERON:0002358	90.57	gold quality
left lobe of thyroid gland	UBERON:0001120	90.56	gold quality
right ovary	UBERON:0002118	90.55	gold quality
sural nerve	UBERON:0015488	90.54	gold quality
right lobe of thyroid gland	UBERON:0001119	90.47	gold quality
blood	UBERON:0000178	90.39	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.39	gold quality
zone of skin	UBERON:0000014	90.27	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.27	gold quality
rectum	UBERON:0001052	90.24	gold quality
minor salivary gland	UBERON:0001830	90.24	gold quality
thyroid gland	UBERON:0002046	90.23	gold quality
ascending aorta	UBERON:0001496	90.20	gold quality
thoracic aorta	UBERON:0001515	90.13	gold quality
parietal lobe	UBERON:0001872	90.08	gold quality
ovary	UBERON:0000992	90.04	gold quality
middle temporal gyrus	UBERON:0002771	90.04	gold quality
cortical plate	UBERON:0005343	90.04	gold quality
islet of Langerhans	UBERON:0000006	90.01	gold quality
lower esophagus mucosa	UBERON:0035834	89.89	gold quality
ectocervix	UBERON:0012249	89.88	gold quality
endocervix	UBERON:0000458	89.86	gold quality
descending thoracic aorta	UBERON:0002345	89.86	gold quality
endometrium	UBERON:0001295	89.84	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.84	gold quality
lower esophagus	UBERON:0013473	89.83	gold quality
left coronary artery	UBERON:0001626	89.80	gold quality
granulocyte	CL:0000094	89.78	gold quality
body of uterus	UBERON:0009853	89.78	gold quality
choroid plexus epithelium	UBERON:0003911	89.70	gold quality
esophagus	UBERON:0001043	89.68	gold quality
vagina	UBERON:0000996	89.67	gold quality
esophagus mucosa	UBERON:0002469	89.65	gold quality
mouth mucosa	UBERON:0003729	89.64	gold quality
pituitary gland	UBERON:0000007	89.57	gold quality
pigmented layer of retina	UBERON:0001782	89.53	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.51	gold quality
gingival epithelium	UBERON:0001949	89.49	gold quality
spleen	UBERON:0002106	89.48	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.48	gold quality
entorhinal cortex	UBERON:0002728	89.42	gold quality
upper lobe of left lung	UBERON:0008952	89.41	gold quality
gall bladder	UBERON:0002110	89.40	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.40	gold quality
right coronary artery	UBERON:0001625	89.39	gold quality
amniotic fluid	UBERON:0000173	89.36	gold quality
coronary artery	UBERON:0001621	89.30	gold quality
subcutaneous adipose tissue	UBERON:0002190	89.29	gold quality
body of pancreas	UBERON:0001150	89.11	gold quality
esophagus squamous epithelium	UBERON:0006920	89.09	gold quality
saliva-secreting gland	UBERON:0001044	89.08	gold quality
upper lobe of lung	UBERON:0008948	89.08	gold quality
cartilage tissue	UBERON:0002418	89.05	gold quality
superior frontal gyrus	UBERON:0002661	89.05	gold quality
right lobe of liver	UBERON:0001114	88.90	gold quality
cortex of kidney	UBERON:0001225	88.90	gold quality
sperm	CL:0000019	88.89	gold quality
visceral pleura	UBERON:0002401	88.88	gold quality
female reproductive system	UBERON:0000474	88.84	gold quality
connective tissue	UBERON:0002384	88.80	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.37
E-MTAB-10137	no	164.70

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	48.1
Nucleus accumbens	tissue	42.5
Corpus callosum	tissue	39.8
Caudate putamen	tissue	36.7
Spinal cord	tissue	35.2
Hippocampus	tissue	35.1	low
Medulla oblongata	tissue	34.0
Pons	tissue	33.9
Midbrain	tissue	33.9
Postcentral gyrus	tissue	33.3
Putamen	tissue	32.4
Thalamus	tissue	32.4
Cerebellum	tissue	32.4	medium
Locus coeruleus	tissue	32.4
Superior colliculi	tissue	31.4
Substantia nigra	tissue	31.4
Periaqueductal gray	tissue	31.2
Septum	tissue	30.8
Frontal cortex	tissue	30.2
Ventral forebrain	tissue	29.8
Hippocampal formation	tissue	29.7
Hypothalamus	tissue	29.3
Cerebral cortex	tissue	28.2	low
Somatosensory cortex	tissue	28.2
Motor cortex	tissue	27.5
Occipital cortex	tissue	26.6
Basal ganglia	tissue	26.5	low
Retrosplenial and cingulate cortex	tissue	26.4
Entorhinal cortex	tissue	26.2
Amygdala	tissue	25.5
Temporal cortex	tissue	25.4
Retrosplenial cortex	tissue	25.3
Olfactory bulb	tissue	24.9
Prefrontal cortex	tissue	24.4
Insular cortex	tissue	23.8
Thymus	tissue	18.7
Parathyroid gland	tissue	18.4	low
Tongue	tissue	17.7
Testis	tissue	16.7	medium
Placenta	tissue	16.1	high
Tonsil	tissue	15.8	high
Bone marrow	tissue	15.6	high
Breast	tissue	15.3	medium
Retina	tissue	15.3
Ovary	tissue	15.3	high
Epididymis	tissue	15.2	medium
Kidney	tissue	14.9	medium
Rectum	tissue	14.5	high
Urinary bladder	tissue	14.5	medium
Endometrium 1	tissue	14.1	low
Adrenal gland	tissue	13.9	high
Thyroid gland	tissue	13.8	medium
Seminal vesicle	tissue	13.4	medium
Smooth muscle	tissue	13.0	high
Liver	tissue	12.7	high
Cervix	tissue	12.6	high
Spleen	tissue	12.6	low
Esophagus	tissue	12.5	high
Colon	tissue	12.1	high
Lymph node	tissue	12.0	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Cerebellar cortex (58.7), Vermis (53.1), Flocculonodular lobe (51.8), Corpus callosum, genu (white matter) (49.5), Parieto-temporal junction (white matter) (46.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CUX1, DNMT3B, EGR1, ELF1, FOXO3, HIF1A, IRF6, KLF8, KMT2A, MYC, MYOD1, NFE2L2, NFKB, NR0B1, NR0B2, NRG1, PDX1, SPI1, STAT5A, TAL1, TCF3, TP53, TXK, ZBTB16

miRNA regulators (miRDB)

Targeting PIK3C3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

23 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-4699-5P	98.99	67.50	1210
HSA-MIR-4635	98.74	67.63	1339
HSA-MIR-6772-3P	97.04	65.89	784
HSA-MIR-4714-5P	97.04	67.76	955
HSA-MIR-6886-3P	96.96	66.36	844

Functional genomics

gnomAD constraint: pLI 7.92e-11, LOEUF 1, missense Z 1.8 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000262039 splits into 4 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
18:41,955,292–41,995,955	313 / 340.7	0.92	no
18:41,995,956–42,004,519	64 / 118.7	0.54	no
18:42,004,520–42,037,737	256 / 291.0	0.88	no
18:42,037,738–42,081,134	196 / 312.8	0.63	no
DepMap (CRISPR cell-line fitness): dependent in 74.6% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): huH-1 (-1.619), SNU-61 (-1.513), HCC1937 (-1.504), SH-4 (-1.461), EFO-21 (-1.435), HCC1419 (-1.428), YAPC (-1.396), KP-N-SI9s (-1.371), NCI-H1650 (-1.37), SNU-761 (-1.368), NCI-H1581 (-1.366), AU565 (-1.347), SU.86.86 (-1.346), OVISE (-1.326), SNU-387 (-1.306).

Literature-anchored findings (GeneRIF, showing 40)

• Data show that Pros26.4 negatively regulates Hairless at the genetic and molecular level, providing a novel mechanism of positive regulation of Notch signalling. (PMID:16410550)
• lethal phenotype of Dsk2 overexpression could be rescued in a double transgenic line coexpressing Flag-Dsk2 and Flag-p54. Although the double transgenic line was viable and fertile, it did not restore the proteolytic defects. (PMID:21973017)
• Results describe how Mycobacterium tuberculosis toxin lipoarabinomannan causes phagosome maturation arrest, interfering with a calcium/calmodulin phosphatidylinositol (PI)3 kinase hVPS34 cascade. (PMID:12925680)
• Data identify rab7 as an important regulator of late endosomal VPS34 function and link rab7 to the regulation of phosphatidylinositol 3’-kinase cycling between early and late endosomes. (PMID:14617358)
• A promoter mutation in a PI regulator affecting the binding of a POU-type transcription factor may be involved in BD and SZ in a subset of patients. (PMID:15121481)
• hVps34 is a nutrient-regulated lipid kinase that integrates amino acid and glucose inputs to mTOR and S6K1 (PMID:16049009)
• Amino acids mediate mTOR activation by signaling through class 3 PI3K, hVps34. (PMID:16176982)
• Results argue against a role for Beclin 1 as an essential chaperone or adaptor for hVps34 in normal vesicular trafficking, and they support the hypothesis that Beclin 1 functions mainly to engage hVps34 in the autophagic pathway. (PMID:16390869)
• There is a connection between Beclin 1-associated Class III PI3K/Vps34-dependent autophagy, but not VPS, function and the mechanism of Beclin 1 tumor suppressor action in human breast cancer cells. (PMID:16874027)
• study indicates that hVps34 and its product PI(3)P are involved in endosome to Golgi transport of ricin, and that SNX2 and SNX4 are likely to be effectors in this pathway (PMID:17319803)
• the lipid kinase activity of Vps34 has a role in resveratrol-induced apoptosis and in the formation of autophagolysosomes (PMID:18048384)
• our results do support PIK3C3 play a significant role in the etiology of schizophrenia (PMID:18420347)
• SopB mediates PI(3)P production on the SCV indirectly through recruitment of Rab5 and its effector Vps34. (PMID:18725540)
• Class III PI3K Vps34 is responsible for the synthesis of PtdIns(3)P on phagosomes containing either S aureus or E coli. PtdIns(3)P binding to p40(phox) is important for CD18-dependent activation oxidase activation in response to S aureus and E coli (PMID:18755982)
• A phylogenetic study revealing co-evolution of myotubularins phosphoinositides phosphatases with PI 3-kinase class III complex (PMID:18774718)
• hVps34 activity is regulated through its interactions with hVps15, but is independent of Ca2+/CaM. (PMID:18957027)
• was expressed in cancer tissues at 11 times the level of that found in normal tissue; findings suggest that activation of the PI3K-AKT signal pathway is associated with oral carcinogenesis (PMID:19887755)
• Data show that knockdown of Vps34 reduces gossypol-induced autophagy in both MCF-7 human breast adenocarcinoma and HeLa cell lines. (PMID:20529838)
• A specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis, whereas ATG14L, a PI3K-III subunit involved in autophagy, is not required. (PMID:20643123)
• A PIK3C3 promoter variant (rs3813065/-442 C/T) in an independent multiancestral cohort of 478 systemic lupus erythematosus cases and 522 controls, was examined. (PMID:20671926)
• 14-3-3zeta proteins are shown as a negative regulator of autophagy through regulation of a key component of early stages of the autophagy pathway, such as hVps34. (PMID:20885446)
• Pik3c3 is essential for central nervous system neuronal homeostasis and Pik3c3 deletion; CaMKII-Cre transgenic mouse is a useful model for studying pathological changes in progressive forebrain neurodegeneration. (PMID:20955765)
• a critical role of the Rubicon RUN domain in PI3KC3 and autophagy regulation (PMID:21062745)
• Activation of mTOR by leucine or insulin upregulated hVps34. (PMID:21702994)
• Coimmunoprecipitation assay indicated that hepatitis C virus NS4B formed a complex with human Rab5 and Vps34, supporting the notion that Rab5 and Vps34 are involved in NS4B-induced autophagy. (PMID:21835792)
• Though dispensable for autophagy induction, transgenic Vps34 is a critical regulator of naive T cell homeostasis, modulating interleukin (IL)-7 receptor alpha trafficking, signaling, and recycling. (PMID:22021616)
• Class III PI-3-kinase activates phospholipase D in an amino acid-sensing mTORC1 pathway (PMID:22024166)
• Results describe PKD as a novel Vps34 kinase that functions as an effecter of autophagy under oxidative stress. (PMID:22095288)
• conclude that Slamf1 recruits a subset of Vps34-associated proteins, which is involved in membrane fusion and NOX2 regulation (PMID:22493499)
• Via direct interaction with the class III PI-3-kinase (PI3KC3)/Beclin1, DEDD activated autophagy and induced the degradation of Snail and Twist, two master regulators of EMT (PMID:22719072)
• A mechanistic link between amino acid starvation and autophagy induction via the direct activation of the autophagy-specific PIK3C3 kinase. (PMID:24013218)
• Ric-8A co-localized with Vps34 at the midbody. (PMID:24466196)
• Insulin can spatially regulate VPS34 activity through Src-mediated tyrosine phosphorylation. (PMID:24582588)
• NRBF2 regulates macroautophagy as a component of Vps34 Complex I. (PMID:24785657)
• reveal a novel function of GABP in the regulation of autophagy via transcriptional activation of the BECN1-PIK3C3 complex (PMID:25046113)
• VPS34-IN1 will provide a useful tool to decipher the kinase-dependent functions of Vps34, with acute changes in SGK3 phosphorylation and subcellular localization being new biomarkers of Vps34 activity. (PMID:25395352)
• Data indicte that Compound 31 constitutes an optimized class III phosphoinositide 3-kinase Vps34 inhibitor that could be used to investigate cancer biology. (PMID:25402320)
• DNA damage regulates Vps34 complexes and its downstream mechanisms, including autophagy and receptor endocytosis, through SCF (Skp1-Cul1-F-box)-mediated ubiquitination and degradation (PMID:25593308)
• cis-unsaturated fatty acids require neither BECN1 nor PIK3C3 to stimulate the autophagic flux (PMID:25714112)
• High expression of PI3K core complex genes is associated with poor prognosis in chronic lymphocytic leukemia. (PMID:25840748)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pik3c3	ENSDARG00000054829
mus_musculus	Pik3c3	ENSMUSG00000033628
rattus_norvegicus	Pik3c3	ENSRNOG00000017840
drosophila_melanogaster	Pi3K59F	FBGN0015277
caenorhabditis_elegans	vps-34	WBGENE00006932

Paralogs (9): PIK3C2A (ENSG00000011405), PIK3CB (ENSG00000051382), PIK3CG (ENSG00000105851), PIK3CA (ENSG00000121879), PIK3C2B (ENSG00000133056), PIK3C2G (ENSG00000139144), PI4KB (ENSG00000143393), PIK3CD (ENSG00000171608), PI4KA (ENSG00000241973)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2445019) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 55 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased cell proliferation	2
abnormal autophagy	2
abnormal heart morphology	1
enlarged heart	1
abnormal liver morphology	1
enlarged liver	1
pale liver	1
hindlimb paralysis	1
abnormal sensory neuron morphology	1
decreased sensory neuron number	1
decreased body weight	1
decreased body size	1
microphthalmia	1
cataract	1
small lens	1
impaired coordination	1
abnormal posture	1
absent mesoderm	1
failure of primitive streak formation	1
failure to gastrulate	1
decreased embryo size	1
embryonic growth arrest	1
premature death	1
neurodegeneration	1
abnormal CD4-positive, alpha beta T cell morphology	1

+30 more (showing top 25).

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
Candida albicans SC5314	A0A1D8PDV7	99.8%	Diamond
Candida albicans	Q92213	99.8%	Diamond
Glycine max	P42347	97.9%	Diamond
Sus scrofa	Q5D891	97.9%	Diamond
Bos taurus	O02811	94.0%	Diamond
Xenopus laevis	Q6AZN6	92.0%	Diamond
Arabidopsis thaliana	Q0WPX9	85.7%	Diamond
Saccharomyces cerevisiae S288C	P22543	63.7%	Diamond
Nakaseomyces glabratus CBS 138	Q6FSR7	63.7%	Diamond
Dictyostelium discoideum	P54677	54.3%	Diamond
Schizosaccharomyces pombe 972h-	Q9USR3	46.0%	Diamond
Encephalitozoon cuniculi GB-M1	Q8SQY7	42.4%	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
KC6	ncRNA	641516
LINC00907	ncRNA	284260
RIT2	protein-coding	6014
SYT4	protein-coding	6860

Protein

Protein identifiers

Phosphatidylinositol 3-kinase catalytic subunit type 3 — Q8NEB9 (reviewed: Q8NEB9)

Alternative names: Phosphatidylinositol 3-kinase p100 subunit, Phosphoinositide-3-kinase class 3, hVps34

All UniProt accessions (7): A0A0B4J2B1, A8MYT4, Q8NEB9, K7EIV6, K7EKH3, K7ENH3, M0R386

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. As part of PI3KC3-C1, promotes endoplasmic reticulum membrane curvature formation prior to vesicle budding. Involved in regulation of degradative endocytic trafficking and required for the abscission step in cytokinesis, probably in the context of PI3KC3-C2. Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for transport from early to late endosomes. (Microbial infection) Kinase activity is required for SARS coronavirus-2/SARS-CoV-2 replication.

Subunit / interactions. Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex the core of which is composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 associating with additional regulatory/auxiliary subunits to form alternative complex forms. Alternative complex forms containing a fourth regulatory subunit in a mutually exclusive manner are: the PI3K complex I (PI3KC3-C1) containing ATG14, and the PI3K complex II (PI3KC3-C2) containing UVRAG. PI3KC3-C1 displays a V-shaped architecture with PIK3R4 serving as a bridge between PIK3C3 and the ATG14:BECN1 subcomplex. Both, PI3KC3-C1 and PI3KC3-C2, can associate with further regulatory subunits such as RUBCN, SH3GLB1/Bif-1 and AMBRA1. PI3KC3-C1 probably associates with PIK3CB. Interacts with RAB7A in the presence of PIK3R4. Interacts with AMBRA1. Interacts with BECN1P1/BECN2. Interacts with SLAMF1. May be a component of a complex composed of RAB5A (in GDP-bound form), DYN2 and PIK3C3. Interacts with NCKAP1L. Interacts with ATG14; this interaction is increased in the absence of TMEM39A. Interacts with STEEP1; the interaction is STING1-dependent and required for trafficking of STING1 from the endoplasmic reticulum. Interacts with YWHAG. Interacts with ARMC3. Interacts with AHCYL1; the interaction is strongly enhanced by SAH in a dose-dependent manner.

Subcellular location. Midbody. Late endosome. Cytoplasmic vesicle. Autophagosome.

Tissue specificity. Ubiquitously expressed, with a highest expression in skeletal muscle.

Post-translational modifications. Ubiquitinated via ‘Lys-29’- and ‘Lys-48’-linked ubiquitination by UBE3C, promoting its degradation. Deubiquitination by ZRANB1/TRABID promotes its stabilization, leading to autophagosome maturation.

Similarity. Belongs to the PI3/PI4-kinase family.

RefSeq proteins (2): NP_001294949, NP_002638* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000403	PI3/4_kinase_cat_dom	Domain
IPR001263	PI3K_accessory_dom	Domain
IPR002420	PI3K-type_C2_dom	Domain
IPR008290	PI3K_Vps34	Family
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR015433	PI3/4_kinase	Family
IPR016024	ARM-type_fold	Homologous_superfamily
IPR018936	PI3/4_kinase_CS	Conserved_site
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036940	PI3/4_kinase_cat_sf	Homologous_superfamily
IPR042236	PI3K_accessory_sf	Homologous_superfamily
IPR057756	PI3-kinase_type3/VPS34_cat	Domain

Pfam: PF00454, PF00613, PF00792

Enzyme classification (BRENDA)

• EC 2.7.1.137 — phosphatidylinositol 3-kinase (BRENDA: 29 organisms, 131 substrates, 146 inhibitors, 16 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.03–44	7
PHOSPHATIDYLINOSITOL	0.034–64	3
PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE	0.004–15	2
PHOSPHATIDYLINOSITOL 4-PHOSPHATE	0.009–10	2
1,2-DIOCTANOYLPHOSPHATIDYLINOSITOL 4,5-DIPHOSPHA	0.05	1
PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE	0.011	1

Catalyzed reactions (Rhea)

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP + H(+) (RHEA:12709)

UniProt features (123 total): helix 52, strand 27, sequence conflict 23, turn 6, modified residue 5, region of interest 5, domain 3, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

showing 30 of 44 structures by resolution:

PDB	Title	Method	Resolution (Å)
6HOG	Structure of VPS34 LIR motif bound to GABARAP	X-RAY DIFFRACTION	1.26
7RSP	Structure of the VPS34 kinase domain with compound 14	X-RAY DIFFRACTION	1.67
7RSV	Structure of the VPS34 kinase domain with compound 5	X-RAY DIFFRACTION	1.78
7RSJ	Structure of the VPS34 kinase domain with compound 14	X-RAY DIFFRACTION	1.88
4UWH	Discovery of (2S)-8-((3R)-3-Methylmorpholin-4-yl)-1-(3-methyl-2-oxo- …	X-RAY DIFFRACTION	1.93
9NIN	The structure of human Vacuolar Protein Sorting 34 catalytic domain bound to RD-I-86	X-RAY DIFFRACTION	2.01
8RXR	Crystal structure of VPS34 in complex with inhibitor SB02024	X-RAY DIFFRACTION	2.06
9ORM	The structure of human Vacuolar Protein Sorting 34 catalytic domain bound to RD-I-137	X-RAY DIFFRACTION	2.06
6I3U	Optimization of potent and selective ATM inhibitors suitable for a proof-of-concept study …	X-RAY DIFFRACTION	2.09
9ZF4	The structure of human Vacuolar Protein Sorting 34 catalytic domain bound to RD-II-83	X-RAY DIFFRACTION	2.09
9DKP	The structure of human vacuolar protein sorting 34 catalytic domain bound to RD-I-53	X-RAY DIFFRACTION	2.16
3LS8	Crystal structure of human PIK3C3 in complex with …	X-RAY DIFFRACTION	2.25
6HOH	Structure of VPS34 LIR motif (S249E) bound to GABARAP	X-RAY DIFFRACTION	2.25
9E4V	The structure of human vacuolar protein sorting 34 catalytic domain bound to MES	X-RAY DIFFRACTION	2.36
11YC	The structure of human Vacuolar Protein Sorting 34 catalytic domain bound to RD-II-123	X-RAY DIFFRACTION	2.41
11MM	The structure of human Vacuolar Protein Sorting 34 catalytic domain bound to RD-II-81	X-RAY DIFFRACTION	2.69
4UWG	Discovery of (2S)-8-((3R)-3-Methylmorpholin-4-yl)-1-(3-methyl-2-oxo- …	X-RAY DIFFRACTION	2.7
5ANL	Crystal structure of VPS34 in complex with (2S)-8-((3R)-3- …	X-RAY DIFFRACTION	2.7
5ENN	The crystal structure of Human VPS34 in complex with a selective and potent inhibitor	X-RAY DIFFRACTION	2.7
9MHF	Cryo-EM reconstruction of PI3KC3-C1 in complex with Human RAB1A(Q70L)	ELECTRON MICROSCOPY	2.73
3IHY	Human PIK3C3 crystal structure	X-RAY DIFFRACTION	2.8
4PH4	The crystal structure of Human VPS34 in complex with PIK-III	X-RAY DIFFRACTION	2.8
4UWL	Discovery of (2S)-8-((3R)-3-Methylmorpholin-4-yl)-1-(3-methyl-2-oxo- …	X-RAY DIFFRACTION	2.8
4UWK	Discovery of (2S)-8-((3R)-3-Methylmorpholin-4-yl)-1-(3-methyl-2-oxo- …	X-RAY DIFFRACTION	2.83
4OYS	CRYSTAL STRUCTURE OF VPS34 IN COMPLEX WITH SAR405.	X-RAY DIFFRACTION	2.9
4UWF	Discovery of (2S)-8-((3R)-3-Methylmorpholin-4-yl)-1-(3-methyl-2-oxo- …	X-RAY DIFFRACTION	2.99
6YKG	Structure-based exploration of selectivity for ATM inhibitors in Huntingtons disease	X-RAY DIFFRACTION	3.12
9RX5	VPS34-CII (VPS34 199-REIE-202 to 199-AAAA-202 mutant) bound to RAB5A (Q79L)	ELECTRON MICROSCOPY	3.15
9MHG	Cryo EM reconstruction of PI3KC3-C1 in complex with Human RAB1A(Q70L), VPS34 kinase …	ELECTRON MICROSCOPY	3.2
9RX7	VPS34-CI bound to NRBF2 MIT domain (residues 1-79)	ELECTRON MICROSCOPY	3.33

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NEB9-F1	84.01	0.53

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

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 (5)

Type	Positions
Phosphothreonine	163
Phosphoserine	165, 244, 261, 282

Function

Pathways and Gene Ontology

Reactome pathways

11 curated (TAS) of 41; 12 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

41 pathways:

ID	Pathway	Evidence
R-HSA-9920951	Dengue virus modulates apoptosis ⚕	curated
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses ⚕	curated
R-HSA-9679504	Translation of Replicase and Assembly of the Replication Transcription Complex ⚕	curated
R-HSA-983170	Antigen Presentation: Folding, assembly and peptide loading of class I MHC	curated
R-HSA-1632852	Macroautophagy	curated
R-HSA-109704	PI3K Cascade	curated
R-HSA-5668599	RHO GTPases Activate NADPH Oxidases	curated
R-HSA-1660514	Synthesis of PIPs at the Golgi membrane	curated
R-HSA-1660516	Synthesis of PIPs at the early endosome membrane	curated
R-HSA-1660517	Synthesis of PIPs at the late endosome membrane	curated
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-9772572	Early SARS-CoV-2 Infection Events ⚕	—
R-HSA-5663205	Infectious disease ⚕	—
R-HSA-9679506	SARS-CoV Infections ⚕	—
R-HSA-9678108	SARS-CoV-1 Infection ⚕	—
R-HSA-9694516	SARS-CoV-2 Infection ⚕	—
R-HSA-9705683	SARS-CoV-2-host interactions ⚕	—
R-HSA-9694676	Translation of Replicase and Assembly of the Replication Transcription Complex ⚕	electronic
R-HSA-9824446	Viral Infection Pathways ⚕	—
R-HSA-1280218	Adaptive Immune System	—
R-HSA-9612973	Autophagy	—
R-HSA-983169	Class I MHC mediated antigen processing & presentation	—
R-HSA-2428924	IGF1R signaling cascade	—
R-HSA-112399	IRS-mediated signalling	—
R-HSA-2428928	IRS-related events triggered by IGF1R	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-74751	Insulin receptor signalling cascade	—
R-HSA-1430728	Metabolism	—
R-HSA-556833	Metabolism of lipids	—
R-HSA-1483255	PI Metabolism	—
R-HSA-1483257	Phospholipid metabolism	—
R-HSA-195258	RHO GTPase Effectors	—
R-HSA-162582	Signal Transduction	—
R-HSA-74752	Signaling by Insulin receptor	—
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases	—
R-HSA-194315	Signaling by Rho GTPases	—
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3	—
R-HSA-2404192	Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	—
R-HSA-168898	Toll-like Receptor Cascades	—

MSigDB gene sets: 323 (showing top): REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_LYSOSOMAL_TRANSPORT, GOBP_ENDOSOME_ORGANIZATION, GOBP_VACUOLE_ORGANIZATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_RESPONSE_TO_ACID_CHEMICAL, REACTOME_ANTIGEN_PRESENTATION_FOLDING_ASSEMBLY_AND_PEPTIDE_LOADING_OF_CLASS_I_MHC, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION

GO Biological Process (25): autophagosome assembly (GO:0000045), pexophagy (GO:0000425), protein targeting to lysosome (GO:0006622), endocytosis (GO:0006897), autophagy (GO:0006914), endosome organization (GO:0007032), regulation of autophagy (GO:0010506), macroautophagy (GO:0016236), regulation of macroautophagy (GO:0016241), protein processing (GO:0016485), regulation of cytokinesis (GO:0032465), phosphatidylinositol-3-phosphate biosynthetic process (GO:0036092), cellular response to glucose starvation (GO:0042149), response to L-leucine (GO:0043201), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), host-mediated activation of viral genome replication (GO:0044829), early endosome to late endosome transport (GO:0045022), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954), phosphatidylinositol phosphate biosynthetic process (GO:0046854), phosphatidylinositol-mediated signaling (GO:0048015), synaptic vesicle endocytosis (GO:0048488), cell division (GO:0051301), autophagosome maturation (GO:0097352), positive regulation of protein lipidation (GO:1903061), lipid metabolic process (GO:0006629)

GO Molecular Function (9): protein kinase activity (GO:0004672), ATP binding (GO:0005524), 1-phosphatidylinositol-3-kinase activity (GO:0016303), phosphatidylinositol kinase activity (GO:0052742), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), phosphotransferase activity, alcohol group as acceptor (GO:0016773)

GO Cellular Component (23): phagophore assembly site (GO:0000407), cytoplasm (GO:0005737), endosome (GO:0005768), late endosome (GO:0005770), autophagosome (GO:0005776), peroxisome (GO:0005777), cytosol (GO:0005829), plasma membrane (GO:0005886), axoneme (GO:0005930), membrane (GO:0016020), midbody (GO:0030496), phagocytic vesicle membrane (GO:0030670), phosphatidylinositol 3-kinase complex, class III, type I (GO:0034271), phosphatidylinositol 3-kinase complex, class III, type II (GO:0034272), phosphatidylinositol 3-kinase complex, class III (GO:0035032), autolysosome (GO:0044754), presynaptic endosome (GO:0098830), postsynaptic endosome (GO:0098845), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), cytoplasmic vesicle (GO:0031410), phagocytic vesicle (GO:0045335), postsynapse (GO:0098794)

Reactome top-level categories

15 top-level categories:

Category	Pathways
PI Metabolism	3
Immune System	2
IRS-mediated signalling	1
Autophagy	1
Toll-like Receptor Cascades	1
RHO GTPase Effectors	1
SARS-CoV-1 Infection	1
Early SARS-CoV-2 Infection Events	1
SARS-CoV-2-host interactions	1
Class I MHC mediated antigen processing & presentation	1
Dengue Virus-Host Interactions	1
IRS-related events triggered by IGF1R	1
Insulin receptor signalling cascade	1
Phospholipid metabolism	1
Metabolism of lipids	1

GO top-level categories

showing 60 of 79 GO namespaces:

Category	Terms
cellular anatomical structure	6
cytoplasm	3
endosome	3
macroautophagy	2
autophagy	2
phosphotransferase activity, alcohol group as acceptor	2
transferase activity, transferring phosphorus-containing groups	2
phosphatidylinositol 3-kinase complex, class III	2
synapse	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
autophagy of peroxisome	1
protein targeting to vacuole	1
lysosomal transport	1
protein localization to lysosome	1
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
endomembrane system organization	1
vesicle organization	1
regulation of catabolic process	1
autophagosome assembly	1
regulation of autophagy	1
proteolysis	1
protein maturation	1
cytokinesis	1
regulation of cell cycle process	1
regulation of cell division	1
phosphatidylinositol phosphate biosynthetic process	1
cellular response to starvation	1
response to amino acid	1
response to nitrogen compound	1
response to oxygen-containing compound	1
intracellular signaling cassette	1
host-mediated activation of viral process	1
host-mediated perturbation of viral genome replication	1
vesicle-mediated transport between endosomal compartments	1
positive regulation of leukocyte mediated cytotoxicity	1
positive regulation of natural killer cell mediated immunity	1
natural killer cell mediated cytotoxicity	1
regulation of natural killer cell mediated cytotoxicity	1
glycerophospholipid biosynthetic process	1
intracellular signal transduction	1
kinase activity	1
catalytic activity, acting on a protein	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
phosphatidylinositol-3-phosphate biosynthetic process	1
phosphatidylinositol kinase activity	1
lipid kinase activity	1
nucleoside phosphate binding	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 19 of 57 annotations. The rest are phylogenetic / computational / electronic (IEA).

19 experimentally-supported GO terms:

GO term	NS	Evidence
autophagosome assembly	BP	direct assay
autophagosome maturation	BP	direct assay
autophagy	BP	mutant phenotype
early endosome to late endosome transport	BP	direct assay
host-mediated activation of viral genome replication	BP	direct assay
phosphatidylinositol phosphate biosynthetic process	BP	direct assay
phosphatidylinositol-3-phosphate biosynthetic process	BP	direct assay
positive regulation of natural killer cell mediated cytotoxicity	BP	mutant phenotype
positive regulation of protein lipidation	BP	mutant phenotype
regulation of autophagy	BP	direct assay
regulation of cytokinesis	BP	mutant phenotype
regulation of macroautophagy	BP	direct assay
autolysosome	CC	direct assay
late endosome	CC	direct assay
membrane	CC	high-throughput assay
midbody	CC	direct assay
plasma membrane	CC	direct assay
1-phosphatidylinositol-3-kinase activity	MF	direct assay
phosphatidylinositol kinase activity	MF	direct assay

Protein interactions and networks

STRING

showing 16 of 5,436 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIK3C3	PIK3R4	Q99570	980
PIK3C3	BECN1	Q14457	975
PIK3C3	ATG14	Q6ZNE5	971
PIK3C3	AKT1	P31749	968
PIK3C3	UVRAG	Q9P2Y5	908
PIK3C3	PTEN	P60484	875
PIK3C3	INSR	P06213	873
PIK3C3	EGFR	P00533	864
PIK3C3	GSK3B	P49841	864
PIK3C3	INS	P01308	851
PIK3C3	IRS1	P35568	851
PIK3C3	RUBCN	Q92622	848
PIK3C3	ULK1	O75385	844
PIK3C3	PIK3R1	P27986	840
PIK3C3	AMBRA1	Q9C0C7	836
PIK3C3	ATG5	Q9H1Y0	836

IntAct

Human interaction partners of PIK3C3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

15 partners by confidence:

Partner	Interaction type	MIscore	Records
BECN1	physical association	0.970	18
ATG14	physical association	0.950	4
UVRAG	association	0.940	2
NRBF2	association	0.850	6
RUBCN	physical association	0.830	5
PIK3R4	association	0.830	1
YWHAG	physical association	0.810	3
X	physical association	0.520	2
H1-0	physical association	0.400	1
RAB39A	physical association	0.400	1
HSPA9	association	0.350	1
USP11	association	0.350	1
SMAD4	proximity	0.270	4
AKT1	proximity	0.270	1
GET1	proximity	0.270	1

BioGRID (290 interactions; top human partners by supporting records): BECN1 (Affinity Capture-Western; 62 records), ATG14 (Affinity Capture-Western; 32 records), UVRAG (Affinity Capture-Western; 15 records), PIK3R4 (Co-fractionation; 13 records), NRBF2 (Affinity Capture-MS; 10 records), KIAA0226 (Affinity Capture-Western; 7 records), RAB5A (Proximity Label-MS; 5 records), STYK1 (Affinity Capture-Western; 5 records), ZRANB1 (Affinity Capture-Western; 5 records), GNB2L1 (Affinity Capture-Western; 4 records), OTUD7B (Affinity Capture-Western; 4 records), UBE3C (Affinity Capture-Western; 4 records), FBXL20 (Affinity Capture-Western; 3 records), HSPA1A (Affinity Capture-MS; 3 records), JADE2 (Affinity Capture-MS; 3 records)

SIGNOR signaling

27 signaling interactions:

A	Effect	B	Mechanism
PIK3C3	up-regulates	PTEN	binding
CDK1	down-regulates	PIK3C3	phosphorylation
CDK5	down-regulates	PIK3C3	phosphorylation
UVRAG	“up-regulates activity”	PIK3C3	binding
RUBCN	down-regulates	PIK3C3	binding
3-methyladenine	down-regulates	PIK3C3	“chemical inhibition”
PIK3C3	up-regulates	AKT1	relocalization
PIK3C3	up-regulates	AKT1
CDK5	“down-regulates activity”	PIK3C3	phosphorylation
NRBF2	“down-regulates activity”	PIK3C3	binding
KLHL20	“down-regulates quantity by destabilization”	PIK3C3	binding
“Cullin 3-RBX1-Skp1”	“down-regulates quantity by destabilization”	PIK3C3	polyubiquitination
SRC	“up-regulates activity”	PIK3C3	phosphorylation
PRKD1	“up-regulates activity”	PIK3C3	phosphorylation
ULK1	“up-regulates activity”	PIK3C3	phosphorylation
PIK3C3	up-regulates	“1-phosphatidyl-1D-myo-inositol 3-phosphate”	“chemical modification”
PIK3R4	up-regulates	PIK3C3	binding
PIK3C3	up-regulates	AKT	relocalization
PIK3C3	up-regulates	AKT
PIK3C3	“up-regulates activity”	BECN1	binding
ATG14	“up-regulates activity”	PIK3C3	binding
PIK3R4	“up-regulates activity”	PIK3C3	binding
PIK3C3	“form complex”	“Vps34 Complex I”	binding
PIK3C3	“form complex”	“Vps34 Complex II”	binding
wortmannin	down-regulates	PIK3C3	“chemical inhibition”
LY294002	down-regulates	PIK3C3	“chemical inhibition”
RAB7A	“up-regulates activity”	PIK3C3	“guanine nucleotide exchange factor”

Protein complexes (CORUM) (6)

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

6 complexes by size:

Complex	Subunits	Members
★ VPS34-VPS15-BECLIN1-UVRAG-BCL2 complex	5	UVRAG, BCL2, BECN1, PIK3C3, PIK3R4
Vps34 Complex I	5	ATG14, BECN1, NRBF2, PIK3C3, PIK3R4
VPS34-VPS15-BECLIN1-UVRAG-SLAMF1 complex	5	BECN1, PIK3C3, PIK3R4, SLAMF1, UVRAG
ULK1-ATG13-ATG14-PIK3C3 complex	4	ATG13, ATG14, PIK3C3, ULK1
VPS34-VPS15-BECLIN1-SLAMF1 complex	4	BECN1, PIK3C3, PIK3R4, SLAMF1
PIK3C3-PIK3R4 complex	2	PIK3C3, PIK3R4

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 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
SARS-CoV Infections	5	21.3×	1e-04
Viral Infection Pathways	5	11.8×	8e-04
Infectious disease	5	9.6×	2e-03

Disease & clinical

Genetic variants

Variant evidence for PIK3C3: 112 ClinVar records (0 pathogenic / likely pathogenic); 10 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	4
Benign	3

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 3,126):

Position(s)	Effect	Δscore	Sites
18:41962486	acceptor_gain	1.0000
18:41962487–41962488	acceptor_loss	1.0000	2
18:41962633–41962634	donor_loss	1.0000	5
18:41970325–41970326	acceptor_loss	1.0000	6
18:41970439	donor_gain	1.0000
18:41970457–41970458	donor_loss	1.0000	5
18:41990523	donor_gain	1.0000
18:41993342–41993343	donor_loss	1.0000	5
18:41995989	donor_gain	1.0000
18:41996630	acceptor_gain	1.0000

AlphaMissense

3,296 missense substitutions predicted likely pathogenic (of 5,870 scored), across 680 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
M823	9	0.987	0.999
M172	9	0.962	0.996
M654	9	0.949	0.998
M516	9	0.946	0.993
M783	9	0.921	0.999
M787	9	0.900	0.996
M218	9	0.898	0.991
M617	9	0.870	0.989
D194	8	0.999	1.000
D644	8	0.999	1.000
D761	8	0.999	1.000
D639	8	0.998	1.000
D640	8	0.998	0.999
D743	8	0.998	1.000
H745	8	0.998	0.999
D769	8	0.998	0.999
H759	8	0.997	0.999
N748	8	0.996	1.000
H879	8	0.996	1.000
D830	8	0.995	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.08e-05
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000504
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.00098

Disease associations

OMIM: gene MIM:602609 | disease phenotypes:

GWAS associations

10 associations:

Study	Trait	p-value
GCST010988_179	Adult body size	2e-11
GCST010989_280	Body size at age 10	3e-11
GCST007325_281	General risk tolerance (MTAG)	1e-9
GCST90020053_14	Frailty index	6e-9
GCST012090_65	Major depressive disorder (MTAG)	1e-8
GCST011122_66	Walking pace	4e-8
GCST007240_12	Obese vs. thin	1e-6
GCST001762_822	Obesity-related traits	2e-6
GCST002136_12	Periodontitis (PAL4Q3)	2e-6
GCST002040_11	Blood trace element (Zn levels)	3e-6

EFO canonical traits (from GWAS)

5 canonical traits:

EFO ID	Trait name
EFO:0005187	C-peptide measurement
EFO:0007041	obese body mass index status
EFO:0008579	risk-taking behaviour
EFO:0009819	comparative body size at age 10, self-reported
EFO:0009885	frailty measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1075165 (SINGLE PROTEIN), CHEMBL5483084 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 75,594 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

19 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL2216870	IDELALISIB	4	10,756
CHEMBL483254	PANOBINOSTAT	4	12,172
CHEMBL2017974	BUPARLISIB	3	6,850
CHEMBL1879463	DACTOLISIB	3	8,349
CHEMBL592445	GEDATOLISIB	3	3,340
CHEMBL2387080	TASELISIB	3	3,643
CHEMBL4303323	ACALISIB	2	1,291
CHEMBL1922094	APITOLISIB	2	3,224
CHEMBL4558527	AZD-8154	2	19
CHEMBL3218578	BGT-226 FREE BASE	2	3,018
CHEMBL4084907	BIMIRALISIB	2	1,722
CHEMBL3984425	EGANELISIB	2	1,267
CHEMBL1236962	OMIPALISIB	2	4,170
CHEMBL3586404	ONATASERTIB	2	1,138
CHEMBL521851	PICTILISIB	2	6,322
CHEMBL3360203	PILARALISIB	2	2,838
CHEMBL3545097	SAPANISERTIB	2	2,649
CHEMBL2336325	VISTUSERTIB	2	2,054
CHEMBL3112866	SAR-260301	1	772

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phosphatidylinositol 3-kinase family

Most potent curated ligand interactions (10 total), top 10:

Ligand	Action	Affinity	Parameter
SAR405	Inhibition	8.82	pKd
VPS34-IN-1	Inhibition	8.4	pIC50
torin 2	Inhibition	8.07	pIC50
PIK-III	Inhibition	7.74	pIC50
compound 82 [PMID: 21332118]	Inhibition	7.51	pKi
compound 41 [PMID: 31855425]	Inhibition	7.2	pIC50
compound 5 [PMID: 34779204]	Inhibition	7.08	pIC50
SAR260301	Inhibition	6.74	pIC50
PQR620	Inhibition	5.56	pKd
compound 12b [PMID: 31465220]	Inhibition	5.49	pKd

Binding affinities (BindingDB)

811 measured of 1386 human assays (1388 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
17-hydroxywortmannin	IC50	0.5 nM
CHEMBL5286775	KD	0.53 nM
Sapanisertib	IC50	1 nM	US-10172858: Combination pharmaceutical compositions and uses thereof
6-[(2S)-2-(3-methoxyphenyl)piperidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]piperidin-2-one	IC50	1 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
CHEMBL4561242	IC50	1.6 nM
CHEMBL5192406	IC50	1.7 nM
CHEMBL3913354	IC50	2 nM
CHEMBL4586628	IC50	2 nM
CHEMBL4517404	IC50	2 nM
CHEMBL4556087	KD	2 nM
CHEMBL4639853	IC50	2 nM
4-[(3R)-3-methylmorpholin-4-yl]-6-[(2S)-2-(trifluoromethyl)piperidin-1-yl]piperidin-2-one	IC50	2 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
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
CHEMBL1738719	IC50	2.3 nM
CHEMBL1914726	IC50	2.9 nM
N-(6-(6-Chloro-5-(4-fluorophenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide	IC50	3 nM
CHEMBL4536755	IC50	3 nM
CHEMBL5192215	IC50	3 nM
4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3-(trifluoromethyl)morpholin-4-yl]piperidin-2-one	IC50	3 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
6-[4-acetyl-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one	IC50	3 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
CHEMBL4449047	IC50	3.2 nM
CHEMBL1914743	IC50	3.4 nM
CHEMBL4862803	KI	4 nM
6-[2-(3-methoxyphenyl)pyrrolidin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one	IC50	4 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
(R) and (S) 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one	IC50	4 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
Panobinostat	IC50	5 nM
2-[(1S,2S,5R)-2-benzyl-3-azabicyclo[3.1.0]hexan-3-yl]-4-morpholin-4-yl-1H-pyrimidin-6-one	KI	5 nM	US-11685734: ATM kinase inhibitors and compositions and methods of use thereof
6-[4-(5-fluoropyridine-3-carbonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one	IC50	5 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
N-[4-[2-(3-cyclopropylmorpholin-4-yl)-6-oxopiperidin-4-yl]-2-pyridinyl]acetamide	IC50	5 nM	US-11219618: Pyridylpyridone compounds
CHEMBL1914727	IC50	5.3 nM
CHEMBL5597568	KI	6 nM
6-[(2R)-2-(3-methoxyphenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]piperidin-2-one	IC50	6 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
4-[(3R)-3-methylmorpholin-4-yl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one	IC50	6 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
6-[(2R)-2-(3-methoxyphenyl)piperidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]piperidin-2-one	IC50	6 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
6-[4-[2-(4-fluorophenyl)acetyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one	IC50	6 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
4-(2-Anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one	IC50	6 nM	US-11208423: Pyridinamine-pyridone and pyrimidinamine- pyridone compounds
1-(4-(4-Propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one	IC50	6.3 nM
CHEMBL4470174	IC50	7 nM
CHEMBL4536855	IC50	7 nM
6-[(1S,2S,5R)-2-benzyl-3-azabicyclo[3.1.0]hexan-3-yl]-4-[(2R)-2-methylmorpholin-4-yl]-1H-pyridin-2-one	KI	7 nM	US-11685734: ATM kinase inhibitors and compositions and methods of use thereof
6-(2-chlorophenyl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one	IC50	7 nM	US-11077113: 6-aryl-4-morpholin-1-ylpyridone compounds useful for the treatment of cancer and diabetes
4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one	IC50	7 nM	US-11077113: 6-aryl-4-morpholin-1-ylpyridone compounds useful for the treatment of cancer and diabetes
6-[2-(trifluoromethyl)piperidin-1-yl]-4-[2-[5-(trifluoromethyl)-3-pyridinyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-2-one	IC50	7 nM	US-11498919: Azaindolylpyridone and diazaindolylpyridone compounds
CHEMBL5436994	IC50	7.6 nM
CHEMBL4850755	KI	8 nM
4-[(3R)-3-methylmorpholin-4-yl]-6-[(2R)-2-phenyl-1-piperidyl]-1H-pyridin-2-one	IC50	8 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
6-(2-chlorophenyl)-4-[2-(1,3-oxazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-2-one	IC50	8 nM	US-11498919: Azaindolylpyridone and diazaindolylpyridone compounds
6-[(2R)-2-benzylpyrrolidin-1-yl]-4-morpholin-4-yl-1H-pyridin-2-one	KI	9 nM	US-11685734: ATM kinase inhibitors and compositions and methods of use thereof
CHEMBL5598055	KI	9 nM
4-[(3R)-3-methylmorpholin-4-yl]-6-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyridin-2-one	IC50	9 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes

ChEMBL bioactivities

1042 potent at pChembl≥5 of 1049 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.30	IC50	0.5	nM	CHEMBL273832
9.28	Kd	0.53	nM	CHEMBL5286775
9.00	Kd	1	nM	CHEMBL5404351
9.00	IC50	1	nM	CHEMBL3622372
9.00	IC50	1	nM	CHEMBL5982739
8.96	EC50	1.11	nM	CHEMBL3622372
8.92	IC50	1.2	nM	CHEMBL3622372
8.92	EC50	1.2	nM	CHEMBL3622372
8.82	Kd	1.5	nM	CHEMBL3622372
8.80	IC50	1.585	nM	CHEMBL4561242
8.77	Kd	1.7	nM	CHEMBL2140173
8.77	IC50	1.7	nM	CHEMBL5192406
8.70	IC50	2	nM	CHEMBL4586628
8.70	IC50	2	nM	CHEMBL4517404
8.70	Kd	1.995	nM	CHEMBL4556087
8.70	Kd	2	nM	CHEMBL4794132
8.70	IC50	2	nM	CHEMBL5776423
8.54	IC50	2.9	nM	CHEMBL1914726
8.52	IC50	3	nM	CHEMBL4536755
8.52	IC50	3	nM	CHEMBL5192215
8.52	IC50	3	nM	CHEMBL5786256
8.52	IC50	3	nM	CHEMBL6064351
8.50	IC50	3.162	nM	CHEMBL4449047
8.40	Kd	4	nM	CHEMBL4752634
8.40	Ki	4	nM	CHEMBL4862803
8.40	IC50	3.95	nM	PI-103
8.40	IC50	4	nM	CHEMBL5907047
8.40	IC50	4	nM	CHEMBL5901842
8.38	IC50	4.2	nM	WORTMANNIN
8.30	Ki	5	nM	CHEMBL4857803
8.30	IC50	5	nM	PANOBINOSTAT
8.30	IC50	5	nM	CHEMBL6011558
8.30	IC50	5	nM	CHEMBL6064688
8.30	IC50	5	nM	CHEMBL1914743
8.29	Kd	5.1	nM	CHEMBL4792737
8.28	IC50	5.3	nM	CHEMBL1914727
8.22	Ki	6	nM	CHEMBL4852400
8.22	Ki	6	nM	CHEMBL5597568
8.22	IC50	6	nM	CHEMBL5879383
8.22	IC50	6	nM	CHEMBL5813134
8.22	IC50	6	nM	CHEMBL5941401
8.22	IC50	6	nM	CHEMBL5971543
8.22	IC50	6	nM	CHEMBL5995498
8.15	IC50	7	nM	CHEMBL4470174
8.15	IC50	7	nM	CHEMBL4536855
8.15	EC50	7.03	nM	BGT-226 FREE BASE
8.15	IC50	7	nM	CHEMBL5837613
8.15	IC50	7	nM	CHEMBL5860335
8.15	IC50	7	nM	CHEMBL5983971
8.15	IC50	7	nM	CHEMBL5889154

PubChem BioAssay actives

253 with measured affinity, of 511 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
4-(cyclopropylmethyl)-5-[2-(pyridin-4-ylamino)pyrimidin-4-yl]pyrimidin-2-amine	1512692: Inhibition of Vps34 (unknown origin)	ic50	<0.0001	uM
1-[4-[4-(4-ethylpiperazin-1-yl)anilino]-1,3,5-triazin-2-yl]-1-methyl-3-(2,4,6-trichloro-3,5-dimethoxyphenyl)urea	1937907: Inhibition of PIK3C3 (unknown origin) assessed as dissociation constant	kd	0.0005	uM
[(1R,3R,5S,6S,9R,18S)-6-hydroxy-18-(methoxymethyl)-1,5-dimethyl-11,16-dioxo-13,17-dioxapentacyclo[10.6.1.02,10.05,9.015,19]nonadeca-2(10),12(19),14-trien-3-yl] acetate	1946674: Inhibition of VPS34 (unknown origin)	ic50	0.0005	uM
4-[(3R)-3-methylmorpholin-4-yl]-6-[(2R)-2-(trifluoromethyl)piperidin-1-yl]-1H-pyridin-2-one	2017596: Binding affinity to VPS34 (unknown origin) assessed as dissociation constant by KINOMEscan analysis	kd	0.0010	uM
(8S)-9-[(5-chloro-3-pyridinyl)methyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[1,2-a]pyrimidin-4-one	2074080: Inhibition of human PIK3C3 using PI as substrate by ADP-Glo assay	ic50	0.0010	uM
N-[5-[7-[(2S)-2-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]propoxy]-1,3-dihydro-2-benzofuran-5-yl]-2-methoxy-3-pyridinyl]-2-methoxyethanesulfonamide	1528691: Inhibition of VPS34 in human HL60 cell extract measured after 2 hrs by kinobeads based pull down assay	ic50	0.0016	uM
2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-N-[5-(6-morpholin-4-yl-4-oxopyran-2-yl)-9H-thioxanthen-2-yl]acetamide	1687220: Binding affinity to human Vps34 expressed in mammalian expression system	kd	0.0017	uM
2-[2-(2,4-difluorophenyl)-1,2,4-triazol-3-yl]-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazole-8-carboxamide	1882115: Inhibition of human wild type N-terminal GST tagged VPS34 (1 to 887 end) expressed in baculovirus infected Sf21 insect cells using PI and Phosphatidylserine as substrate preincubated with compound for 20 mins followed by substrate addition measured after 90 mins in presence of ATP by ADP-Glo kinase based luminescence assay	ic50	0.0017	uM
N-[5-[7-[2-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]ethoxy]-1,3-dihydro-2-benzofuran-5-yl]-2-methoxy-3-pyridinyl]methanesulfonamide	1528688: Binding affinity to VPS34 in human HL60 cell extract measured after 2 hrs by kinobeads based pull down assay	kd	0.0020	uM
2-[7-[(2R)-1-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propan-2-yl]oxy-9H-thioxanthen-4-yl]-6-morpholin-4-ylpyran-4-one	1687220: Binding affinity to human Vps34 expressed in mammalian expression system	kd	0.0020	uM
(8S)-9-[(2S)-2-hydroxy-2-phenylethyl]-2-morpholin-4-yl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[1,2-a]pyrimidin-4-one	1512692: Inhibition of Vps34 (unknown origin)	ic50	0.0020	uM
(8S)-2-[(3R)-3-methylmorpholin-4-yl]-9-(3-methyl-2-oxobutyl)-8-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[1,2-a]pyrimidin-4-one	1512692: Inhibition of Vps34 (unknown origin)	ic50	0.0020	uM
N-[2-chloro-5-(4-pyridin-3-ylquinolin-6-yl)-3-pyridinyl]-4-fluorobenzenesulfonamide	628677: Inhibition of human VPS34 assessed as ADP formation using ATP by fluorescence-based immunoassay	ic50	0.0029	uM
N-[6-[4-(2-chlorophenyl)-1,2,4-triazol-3-yl]isoquinolin-3-yl]-2-fluorocyclopropane-1-carboxamide	1882115: Inhibition of human wild type N-terminal GST tagged VPS34 (1 to 887 end) expressed in baculovirus infected Sf21 insect cells using PI and Phosphatidylserine as substrate preincubated with compound for 20 mins followed by substrate addition measured after 90 mins in presence of ATP by ADP-Glo kinase based luminescence assay	ic50	0.0030	uM
(8S)-9-[(2R)-2-hydroxy-2-phenylethyl]-2-morpholin-4-yl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[1,2-a]pyrimidin-4-one	1512692: Inhibition of Vps34 (unknown origin)	ic50	0.0030	uM
N-[5-[7-[(2R)-2-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]propoxy]-1,3-dihydro-2-benzofuran-5-yl]-2-methoxy-3-pyridinyl]-2-methoxyethanesulfonamide	1528691: Inhibition of VPS34 in human HL60 cell extract measured after 2 hrs by kinobeads based pull down assay	ic50	0.0032	uM
6-[(1S,2S,5R)-2-benzyl-3-azabicyclo[3.1.0]hexan-3-yl]-4-morpholin-4-yl-1H-pyridin-2-one	1764612: Inhibition of full length recombinant GST-tagged human VPS34 expressed in baculovirus expression system using PI/PS as substrate incubated for 60 mins in presence of ATP at Km concentration by luminescence assay	ki	0.0040	uM
2-[7-[(2R)-1-methoxypropan-2-yl]oxy-9H-thioxanthen-4-yl]-6-morpholin-4-ylpyran-4-one	1687220: Binding affinity to human Vps34 expressed in mammalian expression system	kd	0.0040	uM
3-(6-morpholin-4-yl-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl)phenol	2159664: Inhibition of human recombinant PI3K Vsp34 in the presence of ATP by scintillation proximity radiometric assay	ic50	0.0040	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	1946674: Inhibition of VPS34 (unknown origin)	ic50	0.0042	uM
2-[(1S,2S,5R)-2-benzyl-3-azabicyclo[3.1.0]hexan-3-yl]-4-morpholin-4-yl-1H-pyrimidin-6-one	1764612: Inhibition of full length recombinant GST-tagged human VPS34 expressed in baculovirus expression system using PI/PS as substrate incubated for 60 mins in presence of ATP at Km concentration by luminescence assay	ki	0.0050	uM
N-[2-chloro-5-(3-morpholin-4-ylquinoxalin-6-yl)-3-pyridinyl]-4-fluorobenzenesulfonamide	628677: Inhibition of human VPS34 assessed as ADP formation using ATP by fluorescence-based immunoassay	ic50	0.0050	uM
Panobinostat	2074080: Inhibition of human PIK3C3 using PI as substrate by ADP-Glo assay	ic50	0.0050	uM
2-(7-methoxy-9H-thioxanthen-4-yl)-6-morpholin-4-ylpyran-4-one	1687220: Binding affinity to human Vps34 expressed in mammalian expression system	kd	0.0051	uM
N-[2-chloro-5-(4-pyridin-4-ylquinolin-6-yl)-3-pyridinyl]-4-fluorobenzenesulfonamide	628677: Inhibition of human VPS34 assessed as ADP formation using ATP by fluorescence-based immunoassay	ic50	0.0053	uM
2-[(2S,3R)-2-benzyl-3-methylpyrrolidin-1-yl]-4-morpholin-4-yl-1H-pyrimidin-6-one	1764612: Inhibition of full length recombinant GST-tagged human VPS34 expressed in baculovirus expression system using PI/PS as substrate incubated for 60 mins in presence of ATP at Km concentration by luminescence assay	ki	0.0060	uM
2-[(2R,3S)-2-benzyl-3-methylpyrrolidin-1-yl]-4-morpholin-4-yl-1H-pyrimidin-6-one	2122163: Binding affinity to Vps34 (unknown origin) assessed as inhibition constant	ki	0.0060	uM
8-(6-methoxy-3-pyridinyl)-3-methyl-1-[4-piperazin-1-yl-3-(trifluoromethyl)phenyl]imidazo[4,5-c]quinolin-2-one	2198496: Inhibition of human VPS34 assessed as reduction in PIP3 product complex formation measured after 30 mins in presence of ATP by quantitative PI3P ELISA assay	ec50	0.0070	uM
(8S)-9-(3,5-difluorophenyl)-2-morpholin-4-yl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[1,2-a]pyrimidin-4-one	1512692: Inhibition of Vps34 (unknown origin)	ic50	0.0070	uM
(8S)-2-morpholin-4-yl-9-(2-propan-2-yloxyethyl)-8-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[1,2-a]pyrimidin-4-one	1512692: Inhibition of Vps34 (unknown origin)	ic50	0.0070	uM
[(2Z)-3-oxo-2-[(E)-3-phenylprop-2-enylidene]-1-benzofuran-6-yl] (E)-3-phenylprop-2-enoate	2017602: Competitive inhibition of VPS34 (unknown origin) incubated for 15 mins in presence of ATP by ELISA	ic50	0.0076	uM
2-[(2R)-2-benzylazepan-1-yl]-4-morpholin-4-yl-1H-pyrimidin-6-one	1764612: Inhibition of full length recombinant GST-tagged human VPS34 expressed in baculovirus expression system using PI/PS as substrate incubated for 60 mins in presence of ATP at Km concentration by luminescence assay	ki	0.0080	uM
9-(6-amino-3-pyridinyl)-1-[3-(trifluoromethyl)phenyl]benzo[h][1,6]naphthyridin-2-one	2198497: Inhibition of human VPS34 assessed as reduction in PIP3 product complex formation	ec50	0.0086	uM
6-[(2R)-2-benzylpyrrolidin-1-yl]-4-morpholin-4-yl-1H-pyridin-2-one	1764612: Inhibition of full length recombinant GST-tagged human VPS34 expressed in baculovirus expression system using PI/PS as substrate incubated for 60 mins in presence of ATP at Km concentration by luminescence assay	ki	0.0090	uM
6-[(2R)-2-benzyl-3-azabicyclo[3.1.0]hexan-3-yl]-4-morpholin-4-yl-1H-pyridin-2-one	2122163: Binding affinity to Vps34 (unknown origin) assessed as inhibition constant	ki	0.0090	uM
2-cyclopropyl-3-[(2,3-dichlorophenyl)methyl]-5-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	2017601: Inhibition of VPS34 (unknown origin) by ADP hunter plus assay	ic50	0.0091	uM
N-[2-chloro-5-(4-morpholin-4-ylquinolin-6-yl)-3-pyridinyl]-4-fluorobenzenesulfonamide	628677: Inhibition of human VPS34 assessed as ADP formation using ATP by fluorescence-based immunoassay	ic50	0.0110	uM
N-[4-[(7R)-4-oxo-7-propan-2-yl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-2-yl]-2-pyridinyl]cyclopropanecarboxamide	1882115: Inhibition of human wild type N-terminal GST tagged VPS34 (1 to 887 end) expressed in baculovirus infected Sf21 insect cells using PI and Phosphatidylserine as substrate preincubated with compound for 20 mins followed by substrate addition measured after 90 mins in presence of ATP by ADP-Glo kinase based luminescence assay	ic50	0.0130	uM
2-morpholin-4-yl-6-[7-[(2R)-1-morpholin-4-ylpropan-2-yl]oxy-9H-thioxanthen-4-yl]pyran-4-one	1687223: Inhibition of recombinant full-length human VPS34 incubated for 60 mins by ADP-Glo kinase assay	ic50	0.0140	uM
4-(cyclopropylmethyl)-N-methyl-5-[2-(pyridin-4-ylamino)pyrimidin-4-yl]pyrimidin-2-amine	1286751: Inhibition of VPS34 in human U2OS cells incubated for 2 hrs by GFP-FYVE reporter gene assay	ic50	0.0140	uM
1-[[4-(cyclopropylmethyl)-5-[2-(pyridin-4-ylamino)pyrimidin-4-yl]pyrimidin-2-yl]amino]-2-methylpropan-2-ol	1286750: Inhibition of recombinant human VPS34 using L-alpha-phosphatidylinositol as substrate incubated for 10 mins by luminescence based ATP detection assay	ic50	0.0150	uM
N-[5-[7-[[(2R)-4-(2-hydroxy-2-methylpropyl)morpholin-2-yl]methoxy]-1,3-dihydro-2-benzofuran-5-yl]-2-methoxy-3-pyridinyl]methanesulfonamide	1528691: Inhibition of VPS34 in human HL60 cell extract measured after 2 hrs by kinobeads based pull down assay	ic50	0.0158	uM
2-[(2R)-2-benzylpyrrolidin-1-yl]-4-morpholin-4-yl-1H-pyrimidin-6-one	1764612: Inhibition of full length recombinant GST-tagged human VPS34 expressed in baculovirus expression system using PI/PS as substrate incubated for 60 mins in presence of ATP at Km concentration by luminescence assay	ki	0.0160	uM
(1R,5S,9R,18S)-18-(methoxymethyl)-1,5-dimethyl-13,17-dioxapentacyclo[10.6.1.02,10.05,9.015,19]nonadeca-2(10),12(19),14-triene-6,11,16-trione	1946674: Inhibition of VPS34 (unknown origin)	ic50	0.0170	uM
2-(3-chloro-N-(2-chloroacetyl)-4-methoxyanilino)-N-(2-phenylethyl)-2-thiophen-2-ylacetamide	1662440: Inhibition of Vps34 (unknown origin) interaction with PIK3 assessed as reduction in autophagy by increasing LC3 level	ic50	0.0180	uM
2-amino-N-[5-[5-[(4-tert-butylphenyl)sulfonylamino]-6-chloro-3-pyridinyl]-4-methyl-1,3-thiazol-2-yl]acetamide	1512697: Inhibition of Vps34 (unknown origin) after 60 mins by ADP-Glo assay	ic50	0.0190	uM
6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-2-(4-nitrophenoxy)pyrimidin-4-amine	1662443: Inhibition of Vps34 in human MCF7-LC3 cells	ic50	0.0190	uM
2-amino-N-[5-[5-[(4-tert-butylphenyl)sulfonylamino]-6-chloro-3-pyridinyl]-4-methyl-1,3-thiazol-2-yl]acetamide;hydrochloride	2247074: Inhibition of human recombinant VPS34 by TR-FRET assay	ic50	0.0190	uM
N-[2-methoxy-5-[7-[[(2R)-4-(oxetan-3-yl)morpholin-2-yl]methoxy]-1,3-dihydro-2-benzofuran-5-yl]-3-pyridinyl]methanesulfonamide	1528691: Inhibition of VPS34 in human HL60 cell extract measured after 2 hrs by kinobeads based pull down assay	ic50	0.0199	uM
2-morpholin-4-yl-6-[7-(oxetan-3-yloxy)-9H-thioxanthen-4-yl]pyran-4-one	1687223: Inhibition of recombinant full-length human VPS34 incubated for 60 mins by ADP-Glo kinase assay	ic50	0.0200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
3-methyladenine	increases reaction, increases expression, decreases activity, decreases response to substance, affects binding (+1 more)	4
Hydrogen Peroxide	increases reaction, decreases activity, decreases response to substance, increases activity, affects binding (+1 more)	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
aminomethylphosphonic acid (AMPA)	increases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
cypermethrin	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	decreases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	decreases expression, affects cotreatment	1
hydroquinone	decreases expression	1
perfluorobutyric acid	increases expression	1
schizandrin A	decreases phosphorylation, affects reaction	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
nefazodone	affects cotreatment, decreases expression	1
cyfluthrin	increases expression	1
gossypetin	increases reaction, increases expression, affects binding, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
ABT-737	affects cotreatment, increases cleavage, increases reaction	1
bisphenol S	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
malondialdehyde-low density lipoprotein, human	affects binding, decreases reaction, increases reaction, increases expression	1
ceritinib	decreases expression	1
Celecoxib	affects cotreatment, increases cleavage, increases reaction	1

ChEMBL screening assays

233 unique, capped per target: 228 binding, 4 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1100131	Binding	Inhibition of VPS34 at 1 uM	Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the treatment of cancer. — *J Med Chem*
CHEMBL4325291	ADMET	Binding affinity to VPS34 in human HL60 cell extract measured after 2 hrs by kinobeads based pull down assay	Optimization of Orally Bioavailable PI3Kδ Inhibitors and Identification of Vps34 as a Key Selectivity Target. — *J Med Chem*
CHEMBL5209921	Functional	Affinity Phenotypic Cellular interaction (Inhibition of PtdIns(3)P levels (at endosomes probed by suppression of endosomal localization of GFP–2×FYVEHrs; U2OS cells)) EUB0000631a PIK3C3	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomics Library wave 3

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1YC	Abcam A-549 PIK3C3 KO	Cancer cell line	Male
CVCL_D2CI	Abcam HCT 116 PIK3C3 KO	Cancer cell line	Male
CVCL_E3KB	HeLa S3 PIK3C3 KO clone #56	Cancer cell line	Female

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PIK3C3 across ~30M SureChEMBL compounds — explore on Sugi Predict.