Discovery of a selective, covalent IRAK1 inhibitor with antiproliferative activity in MYD88 mutated B-cell lymphoma

JM Hatcher, G Yang, L Wang, SB Ficarro… - ACS Medicinal …, 2020 - ACS Publications
JM Hatcher, G Yang, L Wang, SB Ficarro, S Buhrlage, H Wu, JA Marto, SP Treon, NS Gray
ACS Medicinal Chemistry Letters, 2020ACS Publications
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 …
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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