title: Discovery, synthesis and biochemical profiling of purine-2,6-dione derivatives as inhibitors of the human poly(A)-selective ribonuclease Caf1.
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.
authors: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors: Gopal P
authors: GP
authors: Jadhav
authors: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors: Ishwinder
authors: I
authors: Kaur
authors: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors: Maryati
authors: M
authors: Maryati
authors: 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.
authors: Blessing
authors: B
authors: Airhihen
authors: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK. Electronic address: peter.fischer@nottingham.ac.uk.
authors: Peter M
authors: PM
authors: Fischer
authors: 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: sebastiaan.winkler@nottingham.ac.uk.
authors: G Sebastiaan
authors: GS
authors: Winkler
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011688:Purinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
chemical_list: C489780:CNOT8 protein, human; D011688:Purinones; D014157:Transcription Factors
keywords: Caf1/CNOT7; Deadenylase; Mg(2+) dependent nuclease; PARN; Ribonuclease