compound 12b [PMID: 31465220]   Click here for help

GtoPdb Ligand ID: 10489

Compound class: Synthetic organic
Comment: Compound 12b is a novel conformationally restricted, potent mTOR inhibitor [1]. Although it is an ATP-competitive inhibitor, its novel chemical scaffold dictates it selectivity.
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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 2
Topological polar surface area 102.52
Molecular weight 369.19
XLogP 0.91
No. Lipinski's rules broken 0
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Canonical SMILES Nc1ncc(nc1)c1nc(N2CCOCC2C)c2c(n1)N1CCOCC1C2
Isomeric SMILES Nc1ncc(nc1)c1nc(N2CCOC[C@H]2C)c2c(n1)N1CCOC[C@H]1C2
InChI InChI=1S/C18H23N7O2/c1-11-9-26-4-2-24(11)17-13-6-12-10-27-5-3-25(12)18(13)23-16(22-17)14-7-21-15(19)8-20-14/h7-8,11-12H,2-6,9-10H2,1H3,(H2,19,21)/t11-,12-/m1/s1
Bioactivity Comments
Compound 12b exhibits ∼450-fold selectivity for mTOR over class I PI3K isoforms [1]. It is orally active, metabolically stable and displays minimum brain penetration (this latter attribute indicates a bias for treating systemic tumours).
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
mechanistic target of rapamycin kinase Primary target of this compound Hs Inhibitor Inhibition 7.8 pKd - 1
pKd 7.8 (Kd 1.4x10-8 M) [1]
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha Hs Inhibitor Inhibition 5.8 pKd - 1
pKd 5.8 (Kd 1.6x10-6 M) [1]
phosphatidylinositol 3-kinase catalytic subunit type 3 Hs Inhibitor Inhibition 5.5 pKd - 1
pKd 5.5 (Kd 3.2x10-6 M) [1]
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta Hs Inhibitor Inhibition 5.1 pKd - 1
pKd 5.1 (Kd 7.5x10-6 M) [1]