Structure-based optimization of naphthyridones into potent ATAD2 bromodomain inhibitors

DOI: 10.1021/acs.jmedchem.5b00773
PMID: 26230603

Authors: Paul Bamborough (GlaxoSmithKline) , Chun-Wa Chung (GlaxoSmithKline) , Rebecca C. Furze (GlaxoSmithKline) , Paola Grandi (GlaxoSmithKline) , Anne-Marie Michon (GlaxoSmithKline) , Robert J. Sheppard (GlaxoSmithKline) , Heather Barnett (GlaxoSmithKline) , Hawa Diallo (GlaxoSmithKline) , David P. Dixon (GlaxoSmithKline) , Clement Douault (GlaxoSmithKline) , Emma J. Jones (GlaxoSmithKline) , Bhumika Karamshi (GlaxoSmithKline) , Darren J. Mitchell (GlaxoSmithKline) , Rab K. Prinjha (GlaxoSmithKline) , Christina Rau (GlaxoSmithKline) , Robert J. Watson (GlaxoSmithKline) , Thilo Werner (GlaxoSmithKline) , Emmanuel H. Demont (GlaxoSmithKline)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 58 (15) , PAGES 6151 - 6178

State: Published (Approved)
Published: August 2015

Abstract: ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.

Journal Keywords: Purification; Silica; Mixtures; Chromatography; Nuclear magnetic resonance spectroscopy

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


Instruments: I03-Macromolecular Crystallography

Added On: 30/10/2015 15:33

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)