compound 5 [PMID: 34779204]   Click here for help

GtoPdb Ligand ID: 11843

PDB Ligand
Compound class: Synthetic organic
Comment: This compound is an orally bioavailable and selective inhibitor of the class III phosphoinositide 3-kinase VPS34 [4], that was developed for potential to modulate autophagy, as an anti-tumour mechanism. Development was discontinued due to potential unfavourable on-target toxicity (e.g. GI tract necropsy in rats [3]) arising from sustained inhibition of VPS34 kinase activity. Inhibition of VPS34 or deletion of its gene (PIK3C3) is reported to not only affect autophagy, but also alter cellular energy metabolism and disrupt membrane trafficking, phagocytosis and cytokinesis [1,5]. The mechanism of compound 5's interaction with VPS34 can be used to direct the search for inhibitors for other kinases which avoid VPS34 as an off-target [2].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 5
Hydrogen bond donors 1
Rotatable bonds 1
Topological polar surface area 59.39
Molecular weight 276.16
XLogP 1.63
No. Lipinski's rules broken 0

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES C[C@@H]1COCCN1c1nn2c(c1)C(=O)N[C@@H]1[C@H]2CCC1
Isomeric SMILES C[C@@H]1COCCN1c1nn2[C@@H]3CCC[C@@H]3NC(=O)c2c1
InChI InChI=1S/C14H20N4O2/c1-9-8-20-6-5-17(9)13-7-12-14(19)15-10-3-2-4-11(10)18(12)16-13/h7,9-11H,2-6,8H2,1H3,(H,15,19)/t9-,10+,11-/m1/s1
InChI Key LQBRZKIUSVUXJP-OUAUKWLOSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. Bilanges B, Alliouachene S, Pearce W, Morelli D, Szabadkai G, Chung YL, Chicanne G, Valet C, Hill JM, Voshol PJ et al.. (2017)
Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism.
Nat Commun, 8 (1): 1804. [PMID:29180704]
2. Garcia-Barrantes PM. (2022)
Selective VPS34 Inhibitors: High Efficiency Design by Profiting from Small Structural Differences.
J Med Chem, 65 (17): 11497-11499. [PMID:35998347]
3. 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]
4. Hu DX, Patel S, Chen H, Wang S, Staben ST, Dimitrova YN, Wallweber HA, Lee JY, Chan GKY, Sneeringer CJ et al.. (2022)
Structure-Based Design of Potent, Selective, and Orally Bioavailable VPS34 Kinase Inhibitors.
J Med Chem, 65 (17): 11500-11512. [PMID:34779204]
5. Kuma A, Komatsu M, Mizushima N. (2017)
Autophagy-monitoring and autophagy-deficient mice.
Autophagy, 13 (10): 1619-1628. [PMID:28820286]