2. Academic Validation
  3. Rationally Designed Covalent BCL6 Inhibitor That Targets a Tyrosine Residue in the Homodimer Interface

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

  • ACS Med Chem Lett. 2020 Apr 3;11(6):1269-1273. doi: 10.1021/acsmedchemlett.0c00111.
Mingxing Teng 1 2,  Scott B Ficarro 1 2 3,  Hojong Yoon 1 2,  Jianwei Che 1 2,  Jing Zhou 1,  Eric S Fischer 1 2,  Jarrod A Marto 1 3 4,  Tinghu Zhang 1 2,  Nathanael S Gray 1 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 3 Department of Oncologic Pathology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States.
  • 4 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States.
PMID: 32551010 DOI: 10.1021/acsmedchemlett.0c00111
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.

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