Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins

• Published in: European journal of medicinal chemistry Vol. 182; pp. 111633 - 111653
• Main Authors: Chen, Deheng, Lu, Tian, Yan, Ziqin, Lu, Wenchao, Zhou, Feilong, Lyu, Xilin, Xu, Biling, Jiang, Hualiang, Chen, Kaixian, Luo, Cheng, Zhao, Yujun
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.11.2019; Elsevier
• Subjects: Animals; Azepines - chemical synthesis; Azepines - chemistry; Azepines - pharmacology; BD2; BET protein; Bromodomain; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Crystal structure; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Discovery; Hep G2 Cells; Humans; Life Sciences & Biomedicine; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Molecular; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Pharmacology & Pharmacy; Protein Domains; Proteins - antagonists & inhibitors; Proteins - metabolism; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Science & Technology; Selective; Structure-Activity Relationship; BD2; Bromodomain; BET protein; Selective; Crystal structure; DESIGN; RECOGNITION; BREAST; ACUTE-LEUKEMIA; POTENT; SMALL-MOLECULE INHIBITORS; OPTIMIZATION; HOLE APPROACH; DERIVATIVES; BRD4
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111633

Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases. [Display omitted] •A potent and selectively inhibitor of BET BD2, BY27, has been synthesized.•Two co-crystal structures of BY27/BRD2 BD1 and BY27/BRD2 BD2 have been obtained.•DNA microarray analysis shows gene expression alteration features of BY27.•BY27 is efficacious in MV4-11 mouse tumor xenograft model.•In vivo data suggested BY27 has better safety profile in mice.