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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2019 Aug 22; Vol. 62 (16), pp. 7506-7525. Date of Electronic Publication: 2019 Aug 09. - Publication Year :
- 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.
- Subjects :
- ATPases Associated with Diverse Cellular Activities chemistry
ATPases Associated with Diverse Cellular Activities metabolism
Biophysical Phenomena
Catalytic Domain
DNA-Binding Proteins chemistry
DNA-Binding Proteins metabolism
Humans
Models, Molecular
Molecular Structure
Protein Binding drug effects
Small Molecule Libraries chemistry
Small Molecule Libraries metabolism
ATPases Associated with Diverse Cellular Activities antagonists & inhibitors
DNA-Binding Proteins antagonists & inhibitors
Drug Design
Drug Discovery methods
High-Throughput Screening Assays methods
Protein Domains
Small Molecule Libraries pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 62
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31398032
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.9b00673