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 phosphatidylinositol-3-phosphate biosynthetic process. Acts upstream of or within autophagy and positive regulation of protein lipidation. Located in autolysosome; late endosome; and midbody. Part of phosphatidylinositol 3-kinase complex, class III.

Source: NCBI Gene 5289 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 111 total
• Druggable target: yes — 19 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 74.6% of screened cell lines
• MANE Select transcript: NM_002647

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: 23 — 14 protein_coding, 6 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000262039, ENST00000398870, ENST00000585528, ENST00000586545, ENST00000587261, ENST00000587328, ENST00000587402, ENST00000588156, ENST00000588631, ENST00000589056, ENST00000589550, ENST00000590013, ENST00000590220, ENST00000591011, ENST00000593098, ENST00000858066, ENST00000858067, ENST00000858068, ENST00000858069, ENST00000858070, ENST00000938600, ENST00000959750, ENST00000959751

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.

FANTOM5 promoters (2 alternative TSS)

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

Top tissues by expression

298 total, 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

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

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)

23 targeting PIK3C3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-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

DepMap (CRISPR cell-line fitness): dependent in 74.6% of screened cell lines.

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)

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): Q8NEB9, A0A0B4J2B1, A8MYT4, 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.

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), 1 shown:

• 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 (115 total): helix 43, strand 28, sequence conflict 23, turn 6, modified residue 5, region of interest 5, domain 3, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

42 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6HOG	X-RAY DIFFRACTION	1.26
7RSP	X-RAY DIFFRACTION	1.67
7RSV	X-RAY DIFFRACTION	1.78
7RSJ	X-RAY DIFFRACTION	1.88
4UWH	X-RAY DIFFRACTION	1.93
9NIN	X-RAY DIFFRACTION	2.01
8RXR	X-RAY DIFFRACTION	2.06
9ORM	X-RAY DIFFRACTION	2.06
6I3U	X-RAY DIFFRACTION	2.09
9ZF4	X-RAY DIFFRACTION	2.09
9DKP	X-RAY DIFFRACTION	2.16
3LS8	X-RAY DIFFRACTION	2.25
6HOH	X-RAY DIFFRACTION	2.25
9E4V	X-RAY DIFFRACTION	2.36
11YC	X-RAY DIFFRACTION	2.41
11MM	X-RAY DIFFRACTION	2.69
4UWG	X-RAY DIFFRACTION	2.7
5ANL	X-RAY DIFFRACTION	2.7
5ENN	X-RAY DIFFRACTION	2.7
9MHF	ELECTRON MICROSCOPY	2.73
3IHY	X-RAY DIFFRACTION	2.8
4PH4	X-RAY DIFFRACTION	2.8
4UWL	X-RAY DIFFRACTION	2.8
4UWK	X-RAY DIFFRACTION	2.83
4OYS	X-RAY DIFFRACTION	2.9
4UWF	X-RAY DIFFRACTION	2.99
6YKG	X-RAY DIFFRACTION	3.12
9RX5	ELECTRON MICROSCOPY	3.15
9MHG	ELECTRON MICROSCOPY	3.2
9ZPD	ELECTRON MICROSCOPY	3.38

Predicted structure (AlphaFold)

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

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): 163, 165, 244, 261, 282

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-1632852	Macroautophagy
R-HSA-1660514	Synthesis of PIPs at the Golgi membrane
R-HSA-1660516	Synthesis of PIPs at the early endosome membrane
R-HSA-1660517	Synthesis of PIPs at the late endosome membrane
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-5668599	RHO GTPases Activate NADPH Oxidases
R-HSA-9679504	Translation of Replicase and Assembly of the Replication Transcription Complex
R-HSA-9694676	Translation of Replicase and Assembly of the Replication Transcription Complex
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-983170	Antigen Presentation: Folding, assembly and peptide loading of class I MHC
R-HSA-9920951	Dengue virus modulates apoptosis

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 (29): 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), protein localization to phagophore assembly site (GO:0034497), 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), cellular response to starvation (GO:0009267), type II interferon-mediated signaling pathway (GO:0060333), interleukin-6-mediated signaling pathway (GO:0070102)

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

Rollup of top-10 pathways:

Category	Pathways
PI Metabolism	3
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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	3
endosome	3
macroautophagy	2
autophagy	2
autophagosome assembly	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
vesicle-mediated transport	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
regulation of autophagy	1
proteolysis	1
protein maturation	1
cytokinesis	1
regulation of cell cycle process	1
regulation of cell division	1
intracellular protein localization	1
phosphatidylinositol phosphate biosynthetic process	1
cellular response to starvation	1

Protein interactions and networks

STRING

2842 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIK3C3	ATG14	Q6ZNE5	999
PIK3C3	BECN1	Q14457	999
PIK3C3	PIK3R4	Q99570	999
PIK3C3	AMBRA1	Q9C0C7	999
PIK3C3	UVRAG	Q9P2Y5	999
PIK3C3	RAB5A	P20339	995
PIK3C3	NRBF2	Q96F24	995
PIK3C3	BECN2	A8MW95	994
PIK3C3	RUBCN	Q92622	981
PIK3C3	CALM1	P02593	979
PIK3C3	CALML3	P27482	977
PIK3C3	CALML5	Q9NZT1	977
PIK3C3	BCL2	P10415	976
PIK3C3	CALML6	Q8TD86	975
PIK3C3	CALML4	Q96GE6	975

IntAct

166 interactions, top by confidence:

A	B	Type	Score
ATG14	BECN1	psi-mi:“MI:0915”(physical association)	0.980
BECN1	ATG14	psi-mi:“MI:0914”(association)	0.980
ATG14	BECN1	psi-mi:“MI:0914”(association)	0.980
UVRAG	BECN1	psi-mi:“MI:0915”(physical association)	0.970
BECN1	PIK3C3	psi-mi:“MI:0915”(physical association)	0.970
PIK3C3	BECN1	psi-mi:“MI:0914”(association)	0.970
BECN1	PIK3C3	psi-mi:“MI:0914”(association)	0.970
UVRAG	BECN1	psi-mi:“MI:0914”(association)	0.970

BioGRID (288): PIK3C3 (Affinity Capture-Western), PIK3C3 (Affinity Capture-Western), BECN1 (Affinity Capture-Western), UVRAG (Affinity Capture-Western), ATG14 (Affinity Capture-Western), PIK3C3 (Affinity Capture-Western), PIK3C3 (Reconstituted Complex), ATG14 (Affinity Capture-Western), PIK3C3 (Affinity Capture-Western), PIK3C3 (Affinity Capture-Western), BECN1 (Affinity Capture-Western), PIK3C3 (Affinity Capture-MS), PIK3C3 (Affinity Capture-Western), PIK3C3 (Affinity Capture-Western), PIK3C3 (Affinity Capture-Western)

ESM2 similar proteins: A0A0G2K344, D3ZGS3, F1M386, F1MSG6, F1PBJ0, G5EF51, O00329, O02697, O35242, O35904, O70481, O88763, O94830, P32871, P42336, P42337, P42338, P42339, P42347, P42348, P48736, P50520, P54676, P70600, Q01968, Q14289, Q14BI7, Q16JS8, Q3MHU3, Q3UYK3, Q4KWH5, Q4KWH8, Q5D891, Q5ZI89, Q6AZN6, Q6GQ76, Q6NVF0, Q6PF93, Q7Z392, Q80Y98

Diamond homologs: A0A1D8PDV7, O74630, O88763, P22543, P42339, P42347, P42348, P50520, P54676, Q22258, Q5D891, Q6AZN6, Q6FSR7, Q6FX42, Q6PF93, Q7RZT9, Q8NEB9, Q92213, Q95Q95, Q9VXG8, C5J7W8, O01510, P0CP60, P0CP61, P38110, P42338, Q02099, Q13535, Q61CW2, Q6CAD2, Q6CP76, Q8BKX6, Q8BTI9, Q8SQY7, Q8SSE7, Q96Q15, Q9DE14, Q9FKS4, Q9JKK8, Q9M3G7

SIGNOR signaling

27 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”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 91 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
Activation of BAD and translocation to mitochondria	5	55.2×	5e-06
Activation of BH3-only proteins	5	36.0×	2e-05
Intrinsic Pathway for Apoptosis	5	21.2×	2e-04
Macroautophagy	11	18.4×	6e-09
SARS-CoV-2-host interactions	8	13.8×	2e-05
SARS-CoV-1-host interactions	5	12.7×	2e-03
SARS-CoV-1 Infection	6	12.4×	3e-04
Apoptosis	5	12.2×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
early endosome to late endosome transport	6	48.0×	6e-07
autophagosome maturation	7	30.3×	6e-07
autophagosome assembly	10	27.7×	2e-09
mitophagy	7	27.5×	9e-07
cellular response to glucose starvation	5	20.8×	3e-04
phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	15.6×	2e-04
autophagy	9	12.2×	6e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	70
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

5648 predictions. Top by Δscore:

Variant	Effect	Δscore
18:41955356:AGAT:A	donor_gain	1.0000
18:41955356:AGATG:A	donor_loss	1.0000
18:41955357:GAT:G	donor_gain	1.0000
18:41955357:GATG:G	donor_gain	1.0000
18:41955358:AT:A	donor_gain	1.0000
18:41955358:ATGT:A	donor_loss	1.0000
18:41955359:TG:T	donor_loss	1.0000
18:41955360:G:GA	donor_loss	1.0000
18:41955360:G:GG	donor_gain	1.0000
18:41957568:A:AG	acceptor_gain	1.0000
18:41957569:G:GG	acceptor_gain	1.0000
18:41957569:GA:G	acceptor_gain	1.0000
18:41957756:GAA:G	donor_gain	1.0000
18:41957759:G:GG	donor_gain	1.0000
18:41962484:CATAG:C	acceptor_loss	1.0000
18:41962485:A:AG	acceptor_gain	1.0000
18:41962486:T:G	acceptor_gain	1.0000
18:41962486:TA:T	acceptor_loss	1.0000
18:41962487:A:AG	acceptor_gain	1.0000
18:41962487:A:C	acceptor_loss	1.0000
18:41962487:AGCT:A	acceptor_gain	1.0000
18:41962487:AGCTG:A	acceptor_gain	1.0000
18:41962488:G:GC	acceptor_gain	1.0000
18:41962488:GC:G	acceptor_gain	1.0000
18:41962488:GCT:G	acceptor_gain	1.0000
18:41962488:GCTG:G	acceptor_gain	1.0000
18:41962488:GCTGG:G	acceptor_gain	1.0000
18:41962628:TACGG:T	donor_gain	1.0000
18:41962630:CGG:C	donor_gain	1.0000
18:41962631:GG:G	donor_gain	1.0000

AlphaMissense

5870 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:41957583:G:A	G28R	1.000
18:41957583:G:C	G28R	1.000
18:41957677:T:A	V59D	1.000
18:41962490:T:A	W87R	1.000
18:41962490:T:C	W87R	1.000
18:41962530:T:C	L100P	1.000
18:41970449:T:C	L175P	1.000
18:41987813:T:C	L178P	1.000
18:41987824:C:G	H182D	1.000
18:41987854:T:A	W192R	1.000
18:41987854:T:C	W192R	1.000
18:41987855:G:C	W192S	1.000
18:41987856:G:C	W192C	1.000
18:41987856:G:T	W192C	1.000
18:41987858:T:C	L193P	1.000
18:41987860:G:C	D194H	1.000
18:41987861:A:C	D194A	1.000
18:41987861:A:T	D194V	1.000
18:41987867:T:C	L196S	1.000
18:41987872:T:C	F198L	1.000
18:41987874:T:A	F198L	1.000
18:41987874:T:G	F198L	1.000
18:41990490:T:C	L217P	1.000
18:41995910:A:C	K269N	1.000
18:41995910:A:T	K269N	1.000
18:41995921:T:C	L273P	1.000
18:41995927:G:C	R275P	1.000
18:41995965:C:A	P288T	1.000
18:41995965:C:T	P288S	1.000
18:41995966:C:A	P288H	1.000

dbSNP variants (sampled 300 via entrez): RS1000029849 (18:42031412 C>A,G), RS1000036782 (18:42061701 A>G), RS1000047343 (18:42005670 C>T), RS1000073384 (18:42087239 A>G), RS1000081972 (18:42031055 T>C), RS1000122049 (18:42072413 A>G,T), RS1000145766 (18:42008363 T>C), RS1000147097 (18:41965081 G>A), RS1000169495 (18:42078333 C>A,T), RS1000177353 (18:42007965 CTGTT>C), RS1000211935 (18:42049661 C>T), RS1000224031 (18:41969249 A>G), RS1000230864 (18:42036567 C>G), RS1000235717 (18:41987703 G>A,T), RS1000243248 (18:42030332 G>T)

Disease associations

OMIM: gene MIM:602609 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001762_897	Obesity-related traits	2.000000e-06
GCST002040_11	Blood trace element (Zn levels)	3.000000e-06
GCST002136_10	Periodontitis (PAL4Q3)	2.000000e-06
GCST007240_12	Obese vs. thin	1.000000e-06
GCST007325_84	General risk tolerance (MTAG)	1.000000e-09
GCST010988_75	Adult body size	2.000000e-11
GCST010989_280	Body size at age 10	3.000000e-11
GCST011122_10	Walking pace	4.000000e-08
GCST012090_12	Major depressive disorder (MTAG)	1.000000e-08
GCST90020053_14	Frailty index	6.000000e-09

EFO canonical traits (5, from GWAS)

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

19 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 72,104 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2216870	IDELALISIB	4	10,163
CHEMBL483254	PANOBINOSTAT	4	11,666
CHEMBL1879463	DACTOLISIB	3	7,988
CHEMBL2017974	BUPARLISIB	3	6,568
CHEMBL2387080	TASELISIB	3	3,473
CHEMBL592445	GEDATOLISIB	3	3,177
CHEMBL1236962	OMIPALISIB	2	3,989
CHEMBL1922094	APITOLISIB	2	3,070
CHEMBL2336325	VISTUSERTIB	2	1,961
CHEMBL3218578	BGT-226 FREE BASE	2	2,878
CHEMBL3360203	PILARALISIB	2	2,686
CHEMBL3545097	SAPANISERTIB	2	2,524
CHEMBL3586404	ONATASERTIB	2	1,091
CHEMBL3984425	EGANELISIB	2	1,200
CHEMBL4084907	BIMIRALISIB	2	1,625
CHEMBL4303323	ACALISIB	2	1,227
CHEMBL4558527	AZD-8154	2	19
CHEMBL521851	PICTILISIB	2	6,071
CHEMBL3112866	SAR-260301	1	728

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

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)

525 measured of 991 human assays (991 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
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
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
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
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
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
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
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
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
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
(R) and (S) 6-[2-(3-methoxyphenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one	IC50	10 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-[(3S)-3-methylmorpholin-4-yl]piperidin-2-one	IC50	10 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
6-[(2S)-2-(3-chlorophenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]piperidin-2-one	IC50	10 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-[(2S)-4-(oxolane-2-carbonyl)-2-(trifluoromethyl)piperazin-1-yl]piperidin-2-one	IC50	10 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
6-(2-phenylpyrrolidin-1-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-2-one	IC50	10 nM	US-11498919: Azaindolylpyridone and diazaindolylpyridone compounds
N-[4-[2-oxo-6-[2-(trifluoromethyl)piperidin-1-yl]piperidin-4-yl]-2-pyridinyl]acetamide	IC50	12 nM	US-11219618: Pyridylpyridone compounds
4-[2-[(2-Methylthiazol-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one	IC50	13 nM	US-11208423: Pyridinamine-pyridone and pyrimidinamine- pyridone compounds
4-(3-methylmorphol in-4-yl)-6-(2-phenylpyrrolidin-1-yl)-1H-pyridin-2-one	IC50	20 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
(R) and (S) 6-[2-(3-fluorophenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one	IC50	20 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
6-[(2S)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]piperidin-2-one	IC50	20 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
6-[(2S)-2-(3-methoxyphenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]piperidin-2-one	IC50	20 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-[(2R)-2-phenylpyrrolidin-1-yl]piperidin-2-one	IC50	20 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
(R) and (S) 6-[2-(3-chlorophenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one	IC50	20 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
6-[(2R)-2-(3-chlorophenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]piperidin-2-one	IC50	20 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
6-[2-(3-cyclopropylphenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one	IC50	20 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-[(2R)-4-(oxolane-2-carbonyl)-2-(trifluoromethyl)piperazin-1-yl]piperidin-2-one	IC50	20 nM	US-11179399: 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
N-[4-[2-[2-(2-methoxypropan-2-yl)pyrrolidin-1-yl]-6-oxopiperidin-4-yl]-2-pyridinyl]acetamide	IC50	26 nM	US-11219618: Pyridylpyridone compounds
N-[4-(1-cyclopropylsulfonylpyrazolo[4,5-b]pyridin-6-yl)-2-pyridinyl]acetamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
N-[4-[5-[(2,4-difluorophenyl)sulfonylamino]-6-methyl-3-pyridinyl]-5-methyl-2-pyridinyl]cyclopropanecarboxamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
N-[4-(6-amino-5-benzylsulfonyl-3-pyridinyl)-2-pyridinyl]acetamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
N-[4-[5-(4,4-difluoropiperidin-1-yl)sulfonyl-3-pyridinyl]-2-pyridinyl]acetamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
5-(2-acetamido-4-pyridinyl)-2-amino-N-(cyclopropylmethyl)pyridine-3-carboxamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
N-[4-[6-amino-5-(pyrrolidine-1-carbonyl)-3-pyridinyl]-2-pyridinyl]acetamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
N-[4-[5-[(2,4-difluorophenyl)sulfonylamino]-6-methyl-3-pyridinyl]-2-pyridinyl]-2,2-difluorocyclopropane-1-carboxamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
N-[4-(2-methyl-1,1-dioxo-3,4-dihydropyrido[2,3-e][1,2,4]thiadiazin-7-yl)-2-pyridinyl]acetamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
5-(2-acetamido-4-pyridinyl)-N,N-dimethyl-2-(methylamino)pyridine-3-carboxamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
N-[4-[5-[(2,4-difluorophenyl)sulfonylamino]-6-(dimethylamino)-3-pyridinyl]-2-pyridinyl]acetamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
N-[4-[1-(cyclopropylmethyl)-2,2-dioxo-3H-[1,2,5]thiadiazolo[3,4-b]pyridin-6-yl]-2-pyridinyl]acetamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
N-[4-[5-[(2,4-difluorophenyl)sulfonylamino]-6-(methylamino)-3-pyridinyl]-2-pyridinyl]acetamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
N-[4-(1-methylsulfonylpyrrolo[3,2-b]pyridin-6-yl)-2-pyridinyl]acetamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
N-[4-[6-amino-5-(cyclopropylmethylamino)-3-pyridinyl]-2-pyridinyl]acetamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
methyl N-[4-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-pyridinyl]carbamate	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
methyl N-[4-[1-(cyclopropylmethyl)pyrrolo[3,2-b]pyridin-6-yl]-2-pyridinyl]carbamate	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
N-[4-[5-[benzenesulfonyl(methyl)amino]-6-methyl-3-pyridinyl]-2-pyridinyl]acetamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof
N-[4-(5-pyrrolidin-1-ylsulfonyl-3-pyridinyl)-2-pyridinyl]acetamide	IC50	30 nM	US-9751854: Heteroaryls and uses thereof

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

248 with measured affinity, of 502 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
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
N-(4-imidazo[1,2-a]pyridin-7-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	0.0200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
3-methyladenine	increases expression, decreases activity, decreases response to substance, affects binding, decreases reaction (+1 more)	4
Hydrogen Peroxide	decreases activity, decreases response to substance, increases activity, affects binding, decreases reaction (+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	affects cotreatment, decreases expression	1
hydroquinone	decreases expression	1
perfluorobutyric acid	increases expression	1
schizandrin A	affects reaction, decreases phosphorylation	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
nefazodone	affects cotreatment, decreases expression	1
cyfluthrin	increases expression	1
gossypetin	affects binding, decreases reaction, increases reaction, increases expression	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	increases cleavage, increases reaction, affects cotreatment	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)

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