Discovery of a Selective, Covalent IRAK1 Inhibitor with Antiproliferative Activity in MYD88 Mutated B-Cell Lymphoma

  • ACS Med Chem Lett. 2020 Oct 9;11(11):2238-2243. doi: 10.1021/acsmedchemlett.0c00378.
John M Hatcher  1  2 ,  Guang Yang  3  4 ,  Li Wang  5  6 ,  Scott B Ficarro  7  8 ,  Sara Buhrlage  1  2 ,  Hao Wu  5  6 ,  Jarrod A Marto  7  8 ,  Steven P Treon  3  4 ,  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 & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Longwood Center LC-2209, Boston, Massachusetts 02115, United States.
  • 3. Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute, Boston, Massachusetts 02115, United States.
  • 4. Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 5. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 6. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, United States.
  • 7. Department of Cancer Biology, Department of Oncologic Pathology, Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States.
  • 8. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, United States.
PMID: 33214835 DOI: 10.1021/acsmedchemlett.0c00378
Abstract

Interleukin 1 (IL-1) receptor-associated kinases (IRAKs) are serine/threonine kinases that play critical roles in initiating the innate immune response against foreign pathogens. Additionally, dysregulation of IRAK1 signaling plays a role in neoplastic disorders. For example, IRAK1 was shown to be important for survival and proliferation in many B-cell lymphomas, including Waldenström's macroglobulinemia (WM) and ABC subtype Diffused Large B-cell Lymphoma (DLBCL) cells. Here, we report the discovery of a highly potent and selective covalent inhibitor of IRAK1, JH-X-119-01. Intact protein MS labeling studies confirmed that JH-X-119-01 irreversibly labels IRAK1 at C302. This compound exhibited cytotoxic activity at single digit micromolar concentrations in a panel of WM, DLBCL, and lymphoma cell lines expressing MyD88. Cotreatment of JH-X-119-01 with the Btk Inhibitor ibrutinib resulted in synergistic killing effects in these systems. Taken together, JH-X-119-01 represents a highly selective probe of IRAK1 for further development.

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