Investigation of biaryl heterocycles as inhibitors of Wee1 kinase

Bioorg Med Chem Lett. 2019 Jun 15;29(12):1481-1486. doi: 10.1016/j.bmcl.2019.04.017. Epub 2019 Apr 9.

Abstract

In continuation of our previous research towards the discovery of potent, selective and drug-like Wee1 inhibitors, 2 novel series of biaryl heterocycles were designed, synthesized and evaluated. The new biaryl cores were designed to enable structure-activity exploration of substituents at C-8 or N-8 which were used for tuning compound properties and to improve compound profiles. The lead molecule 33 demonstrated a desirable pharmacokinetic profile and potentiated the anti-proliferative activity of irinotecan in vivo when dosed orally in the human breast MX-1 xenograft model.

Keywords: Cdc2; Cdk1; G1 checkpoint; G2/M checkpoint; Wee1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / metabolism*
  • Heterocyclic Compounds / metabolism*
  • Humans
  • Protein-Tyrosine Kinases / metabolism*
  • Structure-Activity Relationship

Substances

  • Cell Cycle Proteins
  • Heterocyclic Compounds
  • Protein-Tyrosine Kinases
  • WEE1 protein, human