Mingxing Teng, Scott B. Ficarro, Hojong Yoon, Jianwei Che, Jing Zhou, Eric S. Fischer, Jarrod A. Marto, Tinghu Zhang, and Nathanael S. Gray
ACS Medicinal Chemistry Letters Article 2020
DOI: 10.1021/acsmedchemlett.0c00111
B-cell lymphoma 6 (BCL6) is a transcriptional repressor frequently deregulated in lymphoid malignancies. BCL6 engages with number of corepressors, and these protein–protein interactions are being explored as a strategy for drug development. Here, we report the development of an irreversible BCL6 inhibitor TMX-2164 that uses a sulfonyl fluoride to covalently react with the hydroxyl group of Tyrosine 58 located in the lateral groove. TMX-2164 exhibits significantly improved inhibitory activity compared to that of its reversible parental compound and displays sustained target engagement and antiproliferative activity in cells. TMX-2164 therefore represents an example of a tyrosine-directed covalent inhibitor of BCL6 which demonstrates advantages relative to reversible targeting.
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