A qualified success: discovery of a new series of ATAD2 bromodomain inhibitors with a novel binding mode using high-throughput screening and hit qualification

DOI: 10.1021/acs.jmedchem.9b00673

Authors: Paul Bamborough (GlaxoSmithKline Research and Development) , Chun-Wa Chung (GlaxoSmithKline Research and Development) , Emmanuel H. Demont (GlaxoSmithKline Research and Development) , Angela M. Bridges (GlaxoSmithKline Research and Development) , Peter D. Craggs (GlaxoSmithKline Research and Development) , David P. Dixon (GlaxoSmithKline Research and Development) , Peter Francis (GlaxoSmithKline Research and Development) , Rebecca C. Furze (GlaxoSmithKline Research and Development) , Paola Grandi (Cellzome) , Emma J. Jones (GlaxoSmithKline Research and Development) , Bhumika Karamshi (GlaxoSmithKline Research and Development) , Kelly Locke (GlaxoSmithKline Research and Development) , Simon C. C. Lucas (GlaxoSmithKline Research and Development) , Anne-Marie Michon (Cellzome) , Darren J. Mitchell (GlaxoSmithKline Research and Development) , Peter Pogány (GlaxoSmithKline Research and Development) , Rab K. Prinjha (GlaxoSmithKline Research and Development) , Christina Rau (Cellzome) , Ana Maria Roa (GlaxoSmithKline Tres Cantos) , Andrew D. Roberts (GlaxoSmithKline Research and Development) , Robert J. Sheppard (GlaxoSmithKline Research and Development) , Robert J. Watson (GlaxoSmithKline Research and Development)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: August 2019

Abstract: The bromodomain of ATAD2 has proved to be one of the least-tractable proteins within this target class. Here, we describe the discovery of a new class of inhibitors by high-throughput screening and show how the difficulties encountered in establishing a screening triage capable of finding progressible hits were overcome by data-driven optimization. Despite the prevalence of nonspecific hits and an exceptionally low progressible hit rate (0.001%), our optimized hit qualification strategy employing orthogonal biophysical methods enabled us to identify a single active series. The compounds have a novel ATAD2 binding mode with noncanonical features including the displacement of all conserved water molecules within the active site and a halogen-bonding interaction. In addition to reporting this new series and preliminary structure–activity relationship, we demonstrate the value of diversity screening to complement the knowledge-based approach used in our previous ATAD2 work. We also exemplify tactics that can increase the chance of success when seeking new chemical starting points for novel and less-tractable targets.

Journal Keywords: Anions; Drug discovery; Assays; Surface plasmon resonance; Screening assays

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


Instruments: I02-Macromolecular Crystallography

Added On: 12/08/2019 08:25

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)