Rationally Designed Covalent BCL6 Inhibitor That Targets a Tyrosine Residue in the Homodimer Interface.

Abstract:

: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.

journal_name

ACS Med Chem Lett

authors

Teng M,Ficarro SB,Yoon H,Che J,Zhou J,Fischer ES,Marto JA,Zhang T,Gray NS

doi

10.1021/acsmedchemlett.0c00111

subject

Has Abstract

pub_date

2020-04-03 00:00:00

pages

1269-1273

issue

6

issn

1948-5875

journal_volume

11

pub_type

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