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
  • 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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