compound 20f [PMID: 28520415]   

GtoPdb Ligand ID: 9961

Compound class: Synthetic organic
Comment: Compound 20f [PMID: 28520415] is reported as a selective inhibitor of PI3Kδ that was specifically designed as an inhalation drug with potential immunomodulatory effects, and which could be effective as a treatment of airway inflammation [1]. It has limited oral bioavailability and systemic exposure, but is retained in lung tissue in vivo following intratracheal delivery.
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 8
Hydrogen bond donors 2
Rotatable bonds 9
Topological polar surface area 143.82
Molecular weight 584.3
XLogP 5.19
No. Lipinski's rules broken 1
Canonical SMILES N#Cc1c(ncnc1N)NC(c1cc2scc(n2c(=O)c1c1cccc(c1)CN1CCC(CC1)N(CC(C)C)C)C)C
Isomeric SMILES N#Cc1c(ncnc1N)N[C@H](c1cc2scc(n2c(=O)c1c1cccc(c1)CN1CCC(CC1)N(CC(C)C)C)C)C
InChI InChI=1S/C32H40N8OS/c1-20(2)16-38(5)25-9-11-39(12-10-25)17-23-7-6-8-24(13-23)29-26(14-28-40(32(29)41)21(3)18-42-28)22(4)37-31-27(15-33)30(34)35-19-36-31/h6-8,13-14,18-20,22,25H,9-12,16-17H2,1-5H3,(H3,34,35,36,37)/t22-/m0/s1
Bioactivity Comments
Compound 20f inhibits PI3Kδ with an IC50 of ~1.3 nM in a cellular assay [1]. It is selective for PI3Kδ over PI3K&dbeta;, PI3Kα and PI3Kγ. In vitro IC50s for the latter two isoforms are 630 nM and 200 nM respectively. Compound 20f shows no inhibitory activity >50% against a screening panel of 345 kinases. It exhibits no hERG liability (<20% inhibition at 11 μM).
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta Hs Activator Inhibition 9.2 pIC50 - 1
pIC50 9.2 (IC50 6.3x10-10 M) [1]
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta Hs Inhibitor Inhibition 7.1 pIC50 - 1
pIC50 7.1 (IC50 7.94x10-8 M) [1]