Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 6, Pages 1269-1273Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00111
Keywords
BCL6; Protein-protein interactions; Covalent inhibitor; Sulfonyl fluoride
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Funding
- NIH [R01CA233800]
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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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