Discovery, synthesis and biochemical profiling of purine-2,6-dione derivatives as inhibitors of the human poly(A)-selective ribonuclease Caf1

Bioorg Med Chem Lett. 2015 Oct 1;25(19):4219-24. doi: 10.1016/j.bmcl.2015.07.095. Epub 2015 Aug 6.

Abstract

Eukaryotic mRNA contains a 3' poly(A) tail, which plays important roles in the regulation of mRNA stability and translation. Well-characterized enzymes involved in the shortening of the poly(A) tail include the multi-subunit Ccr4-Not deadenylase, which contains the Caf1 (Pop2) and Ccr4 catalytic components, and poly(A)-specific ribonuclease (PARN). Two Mg(2+) ions present in the active sites of these ribonucleases are required for RNA cleavage. Here, we report the discovery, synthesis and biochemical profiling of purine-2,6-dione derivatives as (sub)micromolar inhibitors of Caf1.

Keywords: Caf1/CNOT7; Deadenylase; Mg(2+) dependent nuclease; PARN; Ribonuclease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Purinones / chemical synthesis
  • Purinones / chemistry
  • Purinones / pharmacology*
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors*

Substances

  • CNOT8 protein, human
  • Purinones
  • Transcription Factors