Structure-Based Design of Selective Noncovalent CDK12 Inhibitors

  • ChemMedChem. 2018 Feb 6;13(3):231-235. doi: 10.1002/cmdc.201700695.
Jeffrey W Johannes  1 ,  Christopher R Denz  1 ,  Nancy Su  2 ,  Allan Wu  2 ,  Anna C Impastato  2 ,  Scott Mlynarski  1 ,  Jeffrey G Varnes  1 ,  D Bryan Prince  2 ,  Justin Cidado  1 ,  Ning Gao  2 ,  Malcolm Haddrick  3 ,  Natalie H Jones  2 ,  Shaobin Li  4 ,  Xiuwei Li  4 ,  Yang Liu  4 ,  Toan B Nguyen  2 ,  Nichole O'Connell  2 ,  Emma Rivers  5 ,  Daniel W Robbins  1 ,  Ronald Tomlinson  2 ,  Tieguang Yao  4 ,  Xiahui Zhu  2 ,  Andrew D Ferguson  2 ,  Michelle L Lamb  1 ,  John I Manchester  1 ,  Sylvie Guichard  1
Affiliations
  • 1. Oncology, IMED Biotech Unit, AstraZeneca, Boston, MA, USA.
  • 2. Discovery Sciences, IMED Biotech Unit, AstraZeneca, Boston, MA, USA.
  • 3. Discovery Sciences, IMED Biotech Unit, AstraZeneca Pharmaceuticals LP, Alderley Park, Macclesfield, SK10 4TG, UK.
  • 4. Pharmaron Beijing Co. Ltd., 6 Taihe Road BDA, Beijing, 100176, P.R. China.
  • 5. Discovery Sciences, IMED Biotech Unit, AstraZeneca Pharmaceuticals LP, Unit 310 Darwin Building, Cambridge, CB4 0WG, UK.
PMID: 29266803 DOI: 10.1002/cmdc.201700695
Abstract

Cyclin-dependent kinase (CDK) 12 knockdown via siRNA decreases the transcription of DNA-damage-response genes and sensitizes BRCA wild-type cells to poly(ADP-ribose) polymerase (PARP) inhibition. To recapitulate this effect with a small molecule, we sought a potent, selective CDK12 Inhibitor. Crystal structures and modeling informed hybridization between dinaciclib and SR-3029, resulting in lead compound 5 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]. Further structure-guided optimization delivered a series of selective CDK12 inhibitors, including compound 7 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]. Profiling of this compound across CDK9, 7, 2, and 1 at high ATP concentration, single-point kinase panel screening against 352 targets at 0.1 μm, and proteomics via kinase affinity matrix technology demonstrated the selectivity. This series of compounds inhibits phosphorylation of Ser2 on the C-terminal repeat domain of RNA polymerase II, consistent with CDK12 inhibition. These selective compounds were also acutely toxic to OV90 as well as THP1 cells.

Keywords
CDK; kinases; oncology; selectivity; transcription.
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