compound 41 [PMID: 31855425]   Click here for help

GtoPdb Ligand ID: 10598

PDB Ligand Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Compound 41 is a structurally novel, potent, selective and orally bioavailable PI3Kδ inhibitor [1]. Results from this inhibitor optimisation study suggest that off-target inhibition of Vps34 is associated with in vivo toxicity in a rat PK model.
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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 CDK toolkit. 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 9
Hydrogen bond donors 1
Rotatable bonds 11
Topological polar surface area 126.06
Molecular weight 535.2
XLogP 0.78
No. Lipinski's rules broken 1
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.

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Canonical SMILES COCCS(=O)(=O)Nc1cc(cnc1OC)c1cc(OCC2OCCN(C2)C2COC2)c2c(c1)COC2
Isomeric SMILES COCCS(=O)(=O)Nc1cc(cnc1OC)c1cc(OC[C@@H]2OCCN(C2)C2COC2)c2c(c1)COC2
InChI InChI=1S/C25H33N3O8S/c1-31-5-6-37(29,30)27-23-8-18(10-26-25(23)32-2)17-7-19-12-33-16-22(19)24(9-17)36-15-21-11-28(3-4-35-21)20-13-34-14-20/h7-10,20-21,27H,3-6,11-16H2,1-2H3/t21-/m1/s1
InChI Key ZWPJBXLFZFLGMV-OAQYLSRUSA-N
Bioactivity Comments
Compared to other inhibitors in the study (e.g. 19), 41 has lower toxicity and an acceptable pharmacokinetic profile for oral dosing, along with good primary activity and an enhanced selectivity profile [1]. Using the lipid kinobead assay 41 was determined to bind >600-fold more potently to PI3Kδ than to the other class I PI3Ks, and >200-fold more potently to PI3Kδ than to Vps34 (a class III PI3K enzyme).
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta Hs Inhibitor Inhibition 9.7 pKd - 1
⤷ pKd 9.7 (Kd 2x10-10 M) [1]
Description: Apparent binding affinity determined using the lipid kinobead assay.
phosphatidylinositol 3-kinase catalytic subunit type 3 Hs Inhibitor Inhibition 7.2 pKd - 1
⤷ pKd 7.2 (Kd 6.31x10-8 M) [1]
Description: Apparent binding affinity determined using the lipid kinobead assay.
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta Hs Inhibitor Inhibition 8.2 pIC50 - 1
⤷ pIC50 8.2 (IC50 6.31x10-9 M) [1]
phosphatidylinositol 3-kinase catalytic subunit type 3 Hs Inhibitor Inhibition 7.2 pIC50 - 1
⤷ pIC50 7.2 (IC50 6.31x10-8 M) [1]
Description: Determined in a chemoproteomic competition binding assay with antibody-based readout.
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma Hs Inhibitor Inhibition 6.5 pIC50 - 1
⤷ pIC50 6.5 (IC50 3.16x10-7 M) [1]
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha Hs Inhibitor Inhibition 5.8 pIC50 - 1
⤷ pIC50 5.8 (IC50 1.585x10-6 M) [1]
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta Hs Inhibitor Inhibition 5.7 pIC50 - 1
⤷ pIC50 5.7 (IC50 1.995x10-6 M) [1]