CDK12 inhibitor 2   Click here for help

GtoPdb Ligand ID: 10063

Compound class: Synthetic organic
Comment: This compound is a novel and selective cyclin-dependent kinase 12 (CDK12) and CDK13 inhibitor [1]. It is a chemical probe that is suitable for functional studies of CDK12, and a scaffold for further drug discovery efforts. CDK12 is an oncology drug target as its inhibition sensitises cancer cells to DNA-damaging reagents and DNA-repair inhibitors. The chemical structure was generated from the SMILES string supplied with the original J Med Chem article by Ito et al. (2018) [1].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 7
Hydrogen bond donors 2
Rotatable bonds 9
Topological polar surface area 103.05
Molecular weight 532.26
XLogP 6.16
No. Lipinski's rules broken 1
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Canonical SMILES N#Cc1ccc(nc1)NC1CCC(CC1)N(c1ccc(cc1)c1ccc(=O)n(c1)C)C(=O)NCc1ccccc1
Isomeric SMILES N#Cc1ccc(nc1)N[C@@H]1CC[C@H](CC1)N(c1ccc(cc1)c1ccc(=O)n(c1)C)C(=O)NCc1ccccc1
InChI InChI=1S/C32H32N6O2/c1-37-22-26(10-18-31(37)39)25-8-13-28(14-9-25)38(32(40)35-20-23-5-3-2-4-6-23)29-15-11-27(12-16-29)36-30-17-7-24(19-33)21-34-30/h2-10,13-14,17-18,21-22,27,29H,11-12,15-16,20H2,1H3,(H,34,36)(H,35,40)/t27-,29-
Bioactivity Comments
This kinase inhibitor (2) is selective for CDK12/13 over other related C-terminal domain kinases. In a kinome wide-selectivity screen only TAOK1, DYRK2, and STK39 were inhibited by >80% at 1 μM compound. As these kinases play no functional roles in splicing or RNA processing, their inhibition by this compound is unlikely to impact analysis of its use in the investigation of RNA biology. Functional efficacy of inhibitor 2 was demonstrated in vitro by its ability to reduce phosphorylation of RNA polymerase II at its C-terminal domain Ser2 residue in SK-BR-3 cells and to inhibit cell growth [1].
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
cyclin dependent kinase 13 Primary target of this compound Hs Inhibitor Inhibition 8.0 pIC50 - 1
pIC50 8.0 (IC50 1x10-8 M) [1]
cyclin dependent kinase 12 Primary target of this compound Hs Inhibitor Inhibition 7.3 pIC50 - 1
pIC50 7.3 (IC50 5.2x10-8 M) [1]
cyclin dependent kinase 7 Hs Inhibitor Inhibition <5.0 pIC50 - 1
pIC50 <5.0 (IC50 >1x10-5 M) [1]
cyclin dependent kinase 8 Hs Inhibitor Inhibition <5.0 pIC50 - 1
pIC50 <5.0 (IC50 >1x10-5 M) [1]
cyclin dependent kinase 9 Hs Inhibitor Inhibition 4.8 pIC50 - 1
pIC50 4.8 (IC50 1.6x10-5 M) [1]