Design, synthesis, and functional evaluation of triazine-based bivalent agents that simultaneously target the active site and hot spot of phosphatase Cdc25B

Bioorg Med Chem Lett. 2021 Sep 15:48:128265. doi: 10.1016/j.bmcl.2021.128265. Epub 2021 Jul 14.

Abstract

Cdc25B phosphatase catalyzes the dephosphorylation and activation of cyclin-dependent kinases 2 (CDK2/CycA) and their overexpression has been reported in cancers. Although Cdc25B has received much attention as a drug target, its flat and featureless surface makes it challenging to develop new agents targeting this protein. In this study, we investigated the rational design of a series of bivalent triazine-based derivatives with the aim of simultaneously targeting the active site and the remote hotspot critical for the interaction with CDK2/CycA. Compounds 1e and 10, containing aromatic residues, were shown to inhibit Cdc25B activity selectively over Cdc25A at low micromolar concentration.

Keywords: 1,3,5-triazine scaffold; Bivalent inhibitor; Hot-spot; Phosphatase cdc25B; Protein-protein interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Triazines / chemical synthesis
  • Triazines / chemistry
  • Triazines / pharmacology*
  • cdc25 Phosphatases / antagonists & inhibitors*
  • cdc25 Phosphatases / metabolism

Substances

  • Enzyme Inhibitors
  • Triazines
  • CDC25B protein, human
  • cdc25 Phosphatases