Structure-Guided Design and Synthesis of Pyridinone-Based Selective Bromodomain and Extra-Terminal Domain (BET)-First Bromodomain (BD1) Inhibitors

• Published in: Journal of medicinal chemistry 2024-02, Vol.67 (4), p.2712-2731
• Main Authors: Li, Yangfeng, Shen, Zhengnan, Ratia, Kiira, Zhao, Jiong, Huang, Fei, Dubrovyskyii, Oleksii, Indukuri, Divakar, Fu, Jiqiang, Lozano Ramos, Omar, Thatcher, Gregory R. J., Xiong, Rui
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01837

The bromodomain and extra-terminal domain (BET) proteins are epigenetic readers, regulating transcription via two highly homologous tandem bromodomains, BD1 and BD2. Clinical development of nonselective pan-BD BET inhibitors has been challenging, partly due to dose-limiting side effects such as thrombocytopenia. This has prompted the push for domain-selective BET inhibitors to achieve a more favorable therapeutic window. We report a structure-guided drug design campaign that led to the development of a potent BD1-selective BET inhibitor, 33 (XL-126), with a K d of 8.9 nM and 185-fold BD1/BD2 selectivity. The high selectivity was first assayed by SPR, validated by a secondary time-resolved fluorescence energy transfer assay, and further corroborated by BROMOscan (∼57–373 fold selectivity). The cocrystal of 33 with BRD4 BD1 and BD2 demonstrates the source of selectivity: repulsion with His437 and lost binding with the leucine clamp. Notably, the BD1 selectivity of BET inhibitor 33 leads to both the preservation of platelets and potent anti-inflammatory efficacy.