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.
Gopal P Jadhav  1 ,  Ishwinder Kaur  1 ,  Maryati Maryati  1 ,  Blessing Airhihen  2 ,  Peter M Fischer  3 ,  G Sebastiaan Winkler  4
Affiliations
  • 1. School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
  • 2. School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK; School of Pharmacy, University of Nottingham, East Drive, University Park, Nottingham NG7 2RD, UK.
  • 3. School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK. Electronic address: [email protected].
  • 4. School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK; School of Pharmacy, University of Nottingham, East Drive, University Park, Nottingham NG7 2RD, UK. Electronic address: [email protected].
PMID: 26299350 DOI: 10.1016/j.bmcl.2015.07.095
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.
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