Discovery of SHR5428 as a selective and noncovalent inhibitor of CDK7

Bioorg Med Chem Lett. 2023 Sep 1:93:129429. doi: 10.1016/j.bmcl.2023.129429. Epub 2023 Aug 4.

Abstract

Cyclin dependent kinase 7 (CDK7) is an attractive target in tumor indications via regulating both cell cycle and transcription. Here, SHR5428 was discovered as a selective and noncovalent CDK7 inhibitor with highly potent CDK7 enzymatic activity and triple negative breast cancer cellular activity on MDA-MB-468 cell. SHR5428 also displayed favorable pharmacokinetic properties in different preclinical species such as mouse, rat and dog, and showed high selectivity over CDK1, CDK2, CDK4, CDK6, CDK9, CDK12 in CDK family. Furthermore, the computational modeling has shed some light on this mechanism. Additionally the in vivo efficacy study in a breast cancer cell line (HCC70 cell) derived xenograft mouse model proved SHR5428 to be orally efficacious with dose-dependent tumor growth inhibition.

Keywords: CDK7; Efficacy; SAR; Triple negative breast cancer.

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase-Activating Kinase* / antagonists & inhibitors
  • Dogs
  • Humans
  • Mice
  • Phosphorylation
  • Protein Binding
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use
  • Rats

Substances

  • Cyclin-Dependent Kinase-Activating Kinase
  • Protein Kinase Inhibitors
  • CDK7 protein, human