Open AccessRationally Designed Covalent BCL6 Inhibitor That Targets a Tyrosine Residue in the Homodimer Interface
Author(s) -
Mingxing Teng,
Scott B. Ficarro,
Hojong Yoon,
Jianwei Che,
Jing Zhou,
Eric S. Fischer,
Jarrod A. Marto,
Tinghu Zhang,
Nathanael S. Gray
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00111
Subject(s) - bcl6 , covalent bond , residue (chemistry) , chemistry , tyrosine , sulfonyl , cancer research , biochemistry , stereochemistry , biology , b cell , immunology , antibody , organic chemistry , germinal center , alkyl
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.