BRD2-specific inhibitor, BBC0403, inhibits the progression of osteoarthritis pathogenesis in osteoarthritis-induced C57BL/6 male mice.

Autor: Lee H; Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea., Nam J; Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea., Jang H; Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea., Park YS; Benobio Co., Ltd, Seongnam, South Korea., Son MH; Benobio Co., Ltd, Seongnam, South Korea., Lee IH; Benobio Co., Ltd, Seongnam, South Korea., Eyun SI; Department of Life Science, Chung-Ang University, Seoul, South Korea., Yang JH; Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute Harvard Medical School (HMS), Boston, Massachusetts, USA., Jeon J; Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea., Yang S; Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Aug; Vol. 181 (15), pp. 2528-2544. Date of Electronic Publication: 2024 Apr 10.
DOI: 10.1111/bph.16359
Abstrakt: Background and Purpose: The discovery of new bromo- and extra-terminal inhibitors presents new drugs to treat osteoarthritis (OA).
Experimental Approach: The new drug, BBC0403, was identified in the DNA-encoded library screening system by searching for compounds that target BRD (bromodomain-containing) proteins. The binding force with BRD proteins was evaluated using time-resolved fluorescence energy transfer (TR-FRET) and binding kinetics assays. Subsequently, in vitro and ex vivo analyses demonstrated the effects of the BRD2 inhibitor, BBC0403, on OA. For animal experiments, medial meniscus destabilization was performed to create a 12-week-old male C57BL/6 mouse model, and intra-articular (i.a.) injections were administered. Histological and immunohistochemical analyses were then performed. The underlying mechanism was confirmed by gene set enrichment analysis (GSEA) using RNA-seq.
Key Results: TR-FRET and binding kinetics assays revealed that BBC0403 exhibited higher binding specificity for BRD2 compared to BRD3 and BRD4. The anti-OA effects of BBC0403 were tested at concentrations of 5, 10 and 20 μM (no cell toxicity in the range tested). The expression of catabolic factors, prostaglandin E2 (PGE 2 ) production and extracellular matrix (ECM) degradation was reduced. Additionally, the i.a. injection of BBC0403 prevented OA cartilage degradation in mice. Finally, BBC0403 was demonstrated to suppress NF-κB and MAPK signalling pathways.
Conclusion and Implications: This study demonstrated that BBC0403 is a novel BRD2-specific inhibitor and a potential i.a.-injectable therapeutic agent to treat OA.
(© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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