Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 11, Pages 2238-2243Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00378
Keywords
IRAK1; MYD88; Waldenstriim's macroglobulinemia; Diffused Large B-cell Lymphoma; Kinase inhibitor
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Funding
- David and Janet Bingham Research Fund
- Yang Family Fund of the International Waldenstrom's Macroglobulinemia Foundation
- Leukemia and Lymphoma Society [R6507-18]
- NIH SPORE in Multiple Myeloma [2P50CA100707-16A1]
- NIH [R01 CA233800, R01 CA222218, R03 TR002933, R37 AI050872]
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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 Waldenstrom'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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