Discovery of a series of benzopyrimidodiazepinone TNK2 inhibitors via scaffold morphing

Bioorg Med Chem Lett. 2020 Oct 1;30(19):127456. doi: 10.1016/j.bmcl.2020.127456. Epub 2020 Jul 31.

Abstract

The protein kinase TNK2 (ACK1) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role transmitting cell survival, growth and proliferative signals via modification of multiple downstream effectors by unique tyrosine phosphorylation events. Scaffold morphing based on our previous TNK2 inhibitor XMD8-87 identified urea 17 from which we developed the potent and selective compound 32. A co-crystal structure was obtained showing 32 interacting primarily with the main chain atoms of an alanine residue of the hinge region. Additional H-bonds exist between the urea NHs and the Thr205 and Asp270 residues.

Keywords: Benzopyrimidodiazepinone; Kinase inhibitor; Scaffold morphing; TNK2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzodiazepinones / chemical synthesis
  • Benzodiazepinones / metabolism
  • Benzodiazepinones / pharmacology*
  • Cell Line
  • Crystallography, X-Ray
  • Drug Stability
  • Humans
  • Male
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Pyrimidines / chemical synthesis
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Benzodiazepinones
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Tnk2 protein, mouse
  • Protein-Tyrosine Kinases
  • TNK2 protein, human