Cell-active small molecule inhibitors of the DNA-damage repair enzyme poly(ADP-ribose) glycohydrolase (PARG): Discovery and optimization of orally bioavailable quinazolinedione sulfonamides

DOI: 10.1021/acs.jmedchem.8b01407

Authors: Bohdan Waszkowycz (Cancer Research UK Manchester Institute, The University of Manchester) , Kate M. Smith (Cancer Research UK Manchester Institute, The University of Manchester) , Alison E. Mcgonagle (Cancer Research UK Manchester Institute, The University of Manchester) , Allan M. Jordan (Cancer Research UK Manchester Institute, The University of Manchester) , Ben Acton (Cancer Research UK Manchester Institute, The University of Manchester) , Emma Fairweather (Cancer Research UK Manchester Institute, The University of Manchester) , Louise A. Griffiths (Cancer Research UK Manchester Institute, The University of Manchester) , Niall Hamilton (Cancer Research UK Manchester Institute, The University of Manchester) , Nicola Hamilton (Cancer Research UK Manchester Institute, The University of Manchester) , James Hitchin (Cancer Research UK Manchester Institute, The University of Manchester) , Colin P. Hutton (Cancer Research UK Manchester Institute, The University of Manchester) , Dominic James (Cancer Research UK Manchester Institute, The University of Manchester) , Clifford D. Jones (AstraZeneca) , Stuart Jones (Cancer Research UK Manchester Institute, The University of Manchester) , Daniel P. Mould (Cancer Research UK Manchester Institute, The University of Manchester) , Helen Small (Cancer Research UK Manchester Institute, The University of Manchester) , Alexandra Stowell (Cancer Research UK Manchester Institute, The University of Manchester) , Julie Tucker (AstraZeneca) , Ian Waddell (Cancer Research UK Manchester Institute, The University of Manchester) , Donald Ogilvie (Cancer Research UK Manchester Institute, The University of Manchester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: November 2018
Diamond Proposal Number(s): 5994

Abstract: DNA damage repair enzymes are promising targets in the development of new therapeutic agents for a wide range of cancers and potentially other diseases. The enzyme poly(ADP-ribose) glycohydrolase (PARG) plays a pivotal role in the regulation of DNA repair mechanisms; however the lack of potent drug-like inhibitors for use in cellular and in vivo models has limited the investigation of its potential as a novel therapeutic target. Using the crystal structure of human PARG in complex with the weakly active and cytotoxic anthraquinone 8a, novel quinazolinedione sulfonamides PARG inhibitors have been identified by means of structure-based virtual screening and library design. 1-Oxetan-3-ylmethyl derivatives 33d and 35d were selected for preliminary investigations in vivo. X-ray crystal structures help rationalize the observed structure-activity relationships of these novel inhibitors.

Journal Keywords: Reaction products; Crystal structure; Substituents; Noncovalent interactions; Sulfones

Diamond Keywords: Enzymes

Subject Areas: Chemistry, Medicine, Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 14/11/2018 09:56

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)