Structure-guided discovery of a novel, potent, and orally bioavailable 3, 5-dimethylisoxazole aryl-benzimidazole BET bromodomain inhibitor. Issue 3 (1st February 2019)

• Record Type: Journal Article
• Authors: Sperandio, David; Aktoudianakis, Vangelis; Babaoglu, Kerim; Chen, Xiaowu; Elbel, Kristyna; Chin, Gregory; Corkey, Britton; Du, Jinfa; Jiang, Bob; Kobayashi, Tetsuya; Mackman, Richard; Martinez, Ruben; Yang, Hai; Zablocki, Jeff; Kusam, Saritha; Jordan, Kim; Webb, Heather; Bates, Jamie G.; Lad, Latesh; Mish, Michael; Niedziela-Majka, Anita; Metobo, Sammy; Sapre, Annapurna; Hung, Magdeleine; Jin, Debi; Fung, Wanchi; Kan, Elaine; Eisenberg, Gene; Larson, Nate; Newby, Zachary E.R.; Lansdon, Eric; Tay, Chin; Neve, Richard M.; Shevick, Sophia L.; Breckenridge, David G.;
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 3(2019)
• Page Start: 457
• Page End: 469
• Publication Date: 2019-02-01
• Subjects: Antitumor -- BET proteins -- Bromodomain inhibitor -- Epigenetic readers; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.11.020
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: The structure-guided discovery of a novel BET bromodomain inhibitor is disclosed. The lead properties were optimized using in-vitro assays and in-vivo PK studies. The lead compound reduced the in vivo tumor growth two xenograft models. 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.