Discovery of potent and selective CDK8 inhibitors through FBDD approach

  • Bioorg Med Chem Lett. 2017 Sep 15;27(18):4488-4492. doi: 10.1016/j.bmcl.2017.07.080.
Xingchun Han  1 ,  Min Jiang  2 ,  Chengang Zhou  2 ,  Zheng Zhou  3 ,  Zhiheng Xu  3 ,  Lisha Wang  3 ,  Alexander V Mayweg  2 ,  Rui Niu  4 ,  Tai-Guang Jin  4 ,  Song Yang  5
Affiliations
  • 1. Medicinal Chemistry, Roche Innovation Center Shanghai, Bldg 5, 720 Cailun Road, Shanghai 201203, China. Electronic address: [email protected].
  • 2. Medicinal Chemistry, Roche Innovation Center Shanghai, Bldg 5, 720 Cailun Road, Shanghai 201203, China.
  • 3. Chemical Biology, Roche Innovation Center Shanghai, Bldg 5, 720 Cailun Road, Shanghai 201203, China.
  • 4. Discovery Oncology, Roche Innovation Center Shanghai, Bldg 5, 720 Cailun Road, Shanghai 201203, China.
  • 5. Medicinal Chemistry, Roche Innovation Center Shanghai, Bldg 5, 720 Cailun Road, Shanghai 201203, China. Electronic address: [email protected].
PMID: 28802632 DOI: 10.1016/j.bmcl.2017.07.080
Abstract

A fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability.

Keywords
CDK8; Fragment-based drug discovery (FBDD); Inhibitor.
Products