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Publication Abstract from PubMed

Fragment-based ligand discovery has been successful in targeting diverse proteins. Despite drug-like molecules having more 3D character, traditional fragment libraries are largely composed of flat, aromatic fragments. The use of 3D-enriched fragments for enhancing library diversity is underexplored especially against protein-protein interactions. Here, we evaluate using 3D-enriched fragments against bromodomains. Bromodomains are highly ligandable, but selectivity remains challenging, particularly for bromodomain and extraterminal (BET) family bromodomains. We screened a 3D-enriched fragment library against BRD4(D1) via (1)H CPMG NMR with a protein-observed (19)F NMR secondary assay. The screen led to 29% of the hits that are selective over two related bromodomains, BRDT(D1) and BPTF, and the identification of underrepresented chemical bromodomain inhibitor scaffolds. Initial structure-activity relationship studies guided by X-ray crystallography led to a ligand-efficient thiazepane, with good selectivity and affinity for BET bromodomains. These results suggest that the incorporation of 3D-enriched fragments to increase library diversity can benefit bromodomain screening.

Evaluating the Advantages of Using 3D-Enriched Fragments for Targeting BET Bromodomains.,Johnson JA, Nicolaou CA, Kirberger SE, Pandey AK, Hu H, Pomerantz WCK ACS Med Chem Lett. 2019 Nov 22;10(12):1648-1654. doi:, 10.1021/acsmedchemlett.9b00414. eCollection 2019 Dec 12. PMID:31857841^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.