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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)