Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 20, Pages 8073-8088Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm4011302
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Funding
- Cancer Research UK [C309/A11369]
- NHS [C309/A8274.]
- Structural Genomics Consortium [1097737]
- AbbVie, Boehringer Ingelheim
- Canada Foundation for Innovation
- Canadian Institutes for Health Research, Genome Canada
- GlaxoSmithKlline
- Janssen, Lilly Canada
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda
- Wellcome Trust
- Wellcome Trust Career-Development Fellowship [095751/Z/11/Z]
- Cancer Research UK [11566] Funding Source: researchfish
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Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented ICAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent
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