Fragment-based discovery of low-micromolar ATAD2 bromodomain inhibitors

DOI: 10.1021/acs.jmedchem.5b00772
PMID: 26155854

Authors: Emmanuel H. Demont (GlaxoSmithKline) , Chun-Wa Chung (GlaxoSmithKline) , Rebecca C. Furze (GlaxoSmithKline) , Paola Grandi (GlaxoSmithKline) , Anne-Marie Michon (GlaxoSmithKline) , Chris Wellaway (GlaxoSmithKline) , Nathalie Barrett (GlaxoSmithKline) , Angela M. Bridges (GlaxoSmithKline) , Peter D. Craggs (GlaxoSmithKline) , Hawa Diallo (GlaxoSmithKline) , David P. Dixon (GlaxoSmithKline) , Clement Douault (GlaxoSmithKline) , Amanda J. Emmons (GlaxoSmithKline) , Emma J. Jones (GlaxoSmithKline) , Bhumika V. Karamshi (GlaxoSmithKline) , Kelly Locke (GlaxoSmithKline) , Darren J. Mitchell (GlaxoSmithKline) , Bernadette H. Mouzon (GlaxoSmithKline) , Rab K. Prinjha (GlaxoSmithKline) , Paul Bamborough (GlaxoSmithKline)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 58 (14) , PAGES 5649 - 5673

State: Published (Approved)
Published: July 2015

Abstract: Overexpression of ATAD2 (ATPase family, AAA domain containing 2) has been linked to disease severity and progression in a wide range of cancers, and is implicated in the regulation of several drivers of cancer growth. Little is known of the dependence of these effects upon the ATAD2 bromodomain, which has been categorized as among the least tractable of its class. The absence of any potent, selective inhibitors limits clear understanding of the therapeutic potential of the bromodomain. Here, we describe the discovery of a hit from a fragment-based targeted array. Optimization of this produced the first known micromolar inhibitors of the ATAD2 bromodomain.

Journal Keywords: Substituents; Inhibitors; Selectivity; Crystal structure

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


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 30/10/2015 15:02

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)