phosphatidylinositol 3-kinase catalytic subunit type 3 | Phosphatidylinositol 3-kinase family | IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

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phosphatidylinositol 3-kinase catalytic subunit type 3

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
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 18 p12 Pik3c3 phosphatidylinositol 3-kinase
Previous and Unofficial Names
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
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
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
Enzyme Reaction
EC Number: 2.7.1.137

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SAR405 Hs Inhibition 8.8 pKd 9
pKd 8.8 (Kd 1.52x10-9 M) [9]
compound 41 [PMID: 31855425] 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 Hs Inhibition 5.6 pKd 8
pKd 5.6 (Kd 2.75x10-6 M) [8]
compound 12b [PMID: 31465220] Hs Inhibition 5.5 pKd 2
pKd 5.5 (Kd 3.2x10-6 M) [2]
compound 82 [PMID: 21332118] Hs Inhibition 7.5 pKi 4
pKi 7.5 (Ki 3.1x10-8 M) [4]
VPS34-IN-1 Hs Inhibition 8.4 pIC50 10
pIC50 8.4 (IC50 4x10-9 M) [10]
torin 2 Hs Inhibition 8.1 pIC50 7
pIC50 8.1 (IC50 8.58x10-9 M) [7]
PIK-III Hs Inhibition 7.7 pIC50 5
pIC50 7.7 (IC50 1.8x10-8 M) [5]
compound 41 [PMID: 31855425] 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.
SAR260301 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
Immuno Process:  Cellular signalling
General Comments
VPS34 is the only Class III PI 3-kinase (a lipid kinase) identified. Human VPS34 is ubiquitously expressed and is the enzymatic component of a multiprotein complex. VPS34 substrate specificity is limited to phosphatidylinositol. Mammalian VPS34 may be involved in nutrient sensing and autophagy, which permits modulation of cellular activty in response to nutritional changes [1].

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. 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]

8. 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]

9. 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]

10. 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.

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