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phosphatidylinositol 3-kinase catalytic subunit type 3

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Target not currently curated in GtoImmuPdb

Target id: 2152

Nomenclature: phosphatidylinositol 3-kinase catalytic subunit type 3

Abbreviated Name: VPS34

Family: Phosphatidylinositol 3-kinase family, Phosphatidylinositol kinases

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 887 18q12.3 PIK3C3 phosphatidylinositol 3-kinase catalytic subunit type 3
Mouse - 887 18 B1 Pik3c3 phosphatidylinositol 3-kinase catalytic subunit type 3
Rat - 887 18p12 Pik3c3 phosphatidylinositol 3-kinase, catalytic subunit type 3
Previous and Unofficial Names Click here for help
catalytic phosphatidylinositol 3-kinase 3 | phosphatidylinositol 3-kinase | phosphatidylinositol 3-kinase, catalytic subunit type 3 | Phosphatidylinositol 3-kinase p100 subunit | phosphoinositide-3-kinase, class 3 | PI3-kinase type 3 | PI3K type 3 | PI-3K Vps34p | ptdIns-3-kinase type 3
Database Links Click here for help
Alphafold
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Human PIK3C3 crystal structure
PDB Id:  3IHY
Resolution:  2.8Å
Species:  Human
References: 
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human PIK3C3 in complex with 3-[4-(4-Morpholinyl)thieno[3,2-d]pyrimidin-2-yl]-phenol
PDB Id:  3LS8
Resolution:  2.25Å
Species:  Human
References: 
Image of receptor 3D structure from RCSB PDB
Description:  The crystal structure of Human VPS34 in complex with PIK-III
PDB Id:  4PH4
Ligand:  PIK-III
Resolution:  2.8Å
Species:  Human
References:  5
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the VPS34 kinase domain with compound 5
PDB Id:  7RSV
Ligand:  compound 5 [PMID: 34779204]
Resolution:  1.78Å
Species:  Human
References:  7
Enzyme Reaction Click here for help
EC Number: 2.7.1.137

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SAR405 Small molecule or natural product Primary target of this compound Hs Inhibition 8.8 pKd 10
pKd 8.8 (Kd 1.52x10-9 M) [10]
compound 41 [PMID: 31855425] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.2 pKd 6
pKd 7.2 (Kd 6.31x10-8 M) [6]
Description: Apparent binding affinity determined using the lipid kinobead assay.
PQR620 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.6 pKd 9
pKd 5.6 (Kd 2.75x10-6 M) [9]
compound 12b [PMID: 31465220] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.5 pKd 2
pKd 5.5 (Kd 3.2x10-6 M) [2]
compound 82 [PMID: 21332118] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.5 pKi 4
pKi 7.5 (Ki 3.1x10-8 M) [4]
VPS34-IN-1 Small molecule or natural product Primary target of this compound Hs Inhibition 8.4 pIC50 12
pIC50 8.4 (IC50 4x10-9 M) [12]
torin 2 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pIC50 8
pIC50 8.1 (IC50 8.58x10-9 M) [8]
PIK-III Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 7.7 pIC50 5
pIC50 7.7 (IC50 1.8x10-8 M) [5]
compound 41 [PMID: 31855425] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.2 pIC50 6
pIC50 7.2 (IC50 6.31x10-8 M) [6]
Description: Determined in a chemoproteomic competition binding assay with antibody-based readout.
compound 5 [PMID: 34779204] Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.1 pIC50 7
pIC50 7.1 (IC50 8.3x10-8 M) [7]
SAR260301 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.7 pIC50 3
pIC50 6.7 (IC50 1.83x10-7 M) [3]
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Antigen presentation
GO Annotations:  Associated to 1 GO processes
GO:0006897 endocytosis IBA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes
GO:0034162 toll-like receptor 9 signaling pathway TAS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0034162 toll-like receptor 9 signaling pathway TAS
General Comments
VPS34 is the only Class III PI 3-kinase (a lipid kinase) that has been identified. Human VPS34 is ubiquitously expressed and is the enzymatic component of a multiprotein complex. VPS34 substrate specificity is limited to phosphatidylinositol. Mammalian VPS34 plays roles in autophagy, endosomal trafficking, other aspects of membrane biology, and nutrient sensing [1]. VPS34 activity is required for some viruses to replicate in human host cells: e.g. SARS-CoV-2 [13] and hepatitis C virus [11], likely because viruses rely heavily on host cell lipids for replication. Pharmacological inhibition of VPS34 has been shown to reduce SARS-CoV-2 replication in vitro (IC50 ~600 nM) [13].

References

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1. Backer JM. (2008) The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem J, 410 (1): 1-17. [PMID:18215151]

2. Borsari C, Rageot D, Dall'Asen A, Bohnacker T, Melone A, Sele AM, Jackson E, Langlois JB, Beaufils F, Hebeisen P et al.. (2019) A Conformational Restriction Strategy for the Identification of a Highly Selective Pyrimido-pyrrolo-oxazine mTOR Inhibitor. J Med Chem, 62 (18): 8609-8630. [PMID:31465220]

3. Certal V, Carry JC, Halley F, Virone-Oddos A, Thompson F, Filoche-Rommé B, El-Ahmad Y, Karlsson A, Charrier V, Delorme C et al.. (2014) Discovery and optimization of pyrimidone indoline amide PI3Kβ inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers. J Med Chem, 57 (3): 903-20. [PMID:24387221]

4. D'Angelo ND, Kim TS, Andrews K, Booker SK, Caenepeel S, Chen K, D'Amico D, Freeman D, Jiang J, Liu L et al.. (2011) Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors. J Med Chem, 54 (6): 1789-811. [PMID:21332118]

5. Dowdle WE, Nyfeler B, Nagel J, Elling RA, Liu S, Triantafellow E, Menon S, Wang Z, Honda A, Pardee G et al.. (2014) Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat Cell Biol, 16 (11): 1069-79. [PMID:25327288]

6. Henley ZA, Amour A, Barton N, Bantscheff M, Bergamini G, Bertrand SM, Convery M, Down K, Dümpelfeld B, Edwards CD et al.. (2020) Optimization of Orally Bioavailable PI3Kδ Inhibitors and Identification of Vps34 as a Key Selectivity Target. J Med Chem, 63 (2): 638-655. DOI: 10.1021/acs.jmedchem.9b01585 [PMID:31855425]

7. Hu DX, Patel S, Chen H, Wang S, Staben ST, Dimitrova YN, Wallweber HA, Lee JY, Chan GKY, Sneeringer CJ et al.. (2021) Structure-Based Design of Potent, Selective, and Orally Bioavailable VPS34 Kinase Inhibitors. J Med Chem, [Epub ahead of print]. DOI: 10.1021/acs.jmedchem.1c01180 [PMID:34779204]

8. Liu Q, Wang J, Kang SA, Thoreen CC, Hur W, Ahmed T, Sabatini DM, Gray NS. (2011) Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. J Med Chem, 54 (5): 1473-80. [PMID:21322566]

9. Rageot D, Bohnacker T, Melone A, Langlois JB, Borsari C, Hillmann P, Sele AM, Beaufils F, Zvelebil M, Hebeisen P et al.. (2018) Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders. J Med Chem, 61 (22): 10084-10105. [PMID:30359003]

10. Ronan B, Flamand O, Vescovi L, Dureuil C, Durand L, Fassy F, Bachelot MF, Lamberton A, Mathieu M, Bertrand T et al.. (2014) A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat Chem Biol, 10 (12): 1013-9. [PMID:25326666]

11. Su WC, Chao TC, Huang YL, Weng SC, Jeng KS, Lai MM. (2011) Rab5 and class III phosphoinositide 3-kinase Vps34 are involved in hepatitis C virus NS4B-induced autophagy. J Virol, 85 (20): 10561-71. [PMID:21835792]

12. Taracido IC, Harrington EM, Honda A, Keaney E. (2014) Bi-heteroaryl compounds as Vps34 inhibitors. Patent number: US8685993. Assignee: Novartis Ag. Priority date: 21/12/2010. Publication date: 01/04/2014.

13. Williams CG, Jureka AS, Silvas JA, Nicolini AM, Chvatal SA, Carlson-Stevermer J, Oki J, Holden K, Basler CF. (2021) Inhibitors of VPS34 and fatty-acid metabolism suppress SARS-CoV-2 replication. Cell Rep,: 109479 [Epub ahead of print]. DOI: 10.1016/j.celrep.2021.109479 [PMID:34320401]

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