compound 15a [PMID: 32069401]   Click here for help

GtoPdb Ligand ID: 10702

Compound class: Synthetic organic
Comment: Compound 15a is a dual phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor that was designed for potential anti-tumour activity [1]. Dysregulation of the PI3K-Akt-mTOR signalling pathway is often observed in cancers, and simultaneous inhibition of PI3K and mTOR is predicted to offer improved antitumour activity compared to drugs that target single components of the pathway. A number of dual PI3K/mTOR inhibitors are in clinical development (for example gedatolisib, bimiralisib, apitolisib, samotolisib and omipalisib). All of these inhibitors are associated with adverse effects. Compound 15a was designed to address issues around selectivity and toxicity. Unfortunately 15a produced hepatic toxicity in vivo, so further optimisation would be essential to identify a more suitable derivative.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 9
Hydrogen bond donors 1
Rotatable bonds 9
Topological polar surface area 139.37
Molecular weight 610.19
XLogP 4.48
No. Lipinski's rules broken 0
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Canonical SMILES COc1ncc(cc1NS(=O)(=O)c1ccc(cc1F)F)c1ccc2n(c1)c(cn2)c1nnc(o1)CCN1CCN(CC1)C
Isomeric SMILES COc1ncc(cc1NS(=O)(=O)c1ccc(cc1F)F)c1ccc2n(c1)c(cn2)c1nnc(o1)CCN1CCN(CC1)C
InChI InChI=1S/C28H28F2N8O4S/c1-36-9-11-37(12-10-36)8-7-26-33-34-28(42-26)23-16-31-25-6-3-18(17-38(23)25)19-13-22(27(41-2)32-15-19)35-43(39,40)24-5-4-20(29)14-21(24)30/h3-6,13-17,35H,7-12H2,1-2H3
Bioactivity Comments
Compound 15a inhibits PI3Kα in HCT116 cells with an IC50 value of 10 nM [1]. In a DiscoveRX kinase screen against 97 kinases, only 3 hits for 15a were detected; PI3Kα, PI3Kγ (both class I PI3Ks) and the class II enzyme PIK3C2B. Oral administration reduced tumour proliferation in HCT116 and HT-29 xenografts, but its effects were no better than injections of copanlisib in these models. Liver toxicity was observed in the test animals.
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 alpha Hs Inhibitor Inhibition 9.7 pIC50 - 1
pIC50 9.7 (IC50 2x10-10 M) [1]
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta Hs Inhibitor Inhibition 9.3 pIC50 - 1
pIC50 9.3 (IC50 5x10-10 M) [1]
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta Hs Inhibitor Inhibition 9.2 pIC50 - 1
pIC50 9.2 (IC50 5.8x10-10 M) [1]
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma Hs Inhibitor Inhibition 8.9 pIC50 - 1
pIC50 8.9 (IC50 1.2x10-9 M) [1]
mechanistic target of rapamycin kinase Hs Inhibitor Inhibition 7.7 pIC50 - 1
pIC50 7.7 (IC50 2.1x10-8 M) [1]