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  • Title: Structure-guided discovery of a novel, potent, and orally bioavailable 3,5-dimethylisoxazole aryl-benzimidazole BET bromodomain inhibitor.
    Author: Sperandio D, Aktoudianakis V, Babaoglu K, Chen X, Elbel K, Chin G, Corkey B, Du J, Jiang B, Kobayashi T, Mackman R, Martinez R, Yang H, Zablocki J, Kusam S, Jordan K, Webb H, Bates JG, Lad L, Mish M, Niedziela-Majka A, Metobo S, Sapre A, Hung M, Jin D, Fung W, Kan E, Eisenberg G, Larson N, Newby ZER, Lansdon E, Tay C, Neve RM, Shevick SL, Breckenridge DG.
    Journal: Bioorg Med Chem; 2019 Feb 01; 27(3):457-469. PubMed ID: 30606676.
    Abstract:
    The bromodomain and extra-terminal (BET) family of proteins, consisting of the bromodomains containing protein 2 (BRD2), BRD3, BRD4, and the testis-specific BRDT, are key epigenetic regulators of gene transcription and has emerged as an attractive target for anticancer therapy. Herein, we describe the discovery of a novel potent BET bromodomain inhibitor, using a systematic structure-based approach focused on improving potency, metabolic stability, and permeability. The optimized dimethylisoxazole aryl-benzimidazole inhibitor exhibited high potency towards BRD4 and related BET proteins in biochemical and cell-based assays and inhibited tumor growth in two proof-of-concept preclinical animal models.
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