Development of BRD4 inhibitors as anti-inflammatory agents and antidotes for arsenicals. (15th May 2022)

• Record Type: Journal Article
• Authors: Yatchang, Marina Fosso; Mathew, Bini; Srivastava, Ritesh K.; Khan, Jasim; Muzaffar, Suhail; Zhang, Sixue; Wu, Mousheng; Zhai, Ling; Ruiz, Pedro; Agarwal, Anupam; Bostwick, James R.; Suto, Mark J.; Athar, Mohammad; Augelli-Szafran, Corinne E.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 64(2022)
• Publication Date: 2022-05-15
• Subjects: BRD4 Bromodomain 4 -- BET Bromodomain and extra terminal domain -- IL-6 interleukin-6 -- IC50 Half-maximal inhibitory concentration -- CDI Carbonyldiimidazole -- HATU 1-[Bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5-b]pyridinium 3-oxide hexafluorophosphate -- ADME Absorption, Distribution, Metabolism, and Excretion -- HLM Human Liver Microsome, MLM, Mouse Liver Microsome -- PK Pharmacokinetic -- IP Intraperetonial -- Cmax Maximum concentration -- t1/2 Half-life -- tmax Time of peak plasma concentration -- AUClast Area under the curve from the time of dosing to the last measurable concentration -- µM Micromolar -- ITC Isothermal titration calorimetry -- ELISA Enzyme-linked immunoassay -- PAO phenylarsine oxide; Arsenicals -- Antidotes -- Bromodomain 4 -- Inflammation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128696
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Arsenicals belong to the class of chemical warfare agents known as vesicants, which are highly reactive, toxic and cause robust inflammatory response. Cutaneous exposure to arsenicals causes a wide range of systemic organ damage, beginning with cutaneous injuries, and later manifest multi-organ damage and death. Thus, the development of suitable antidotes that can effectively block injury following exposure to these agents is of great importance. Bromodomain 4 (BRD4), a member of the bromodomain and extra terminal domain (BET) family, plays crucial role in regulating transcription of inflammatory, proliferation and cell cycle genes. In this context, the development of potent small molecule inhibitors of BRD4 could serve as potential antidotes for arsenicals. Herein, we describe the synthesis and biological evaluation of a series of compounds.