2. Academic Validation
  3. Structure-Based Design of Selective Noncovalent CDK12 Inhibitors

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112261
    99.86%, CDK Inhibitor
    CDK