Hatcher John M, Yang Guang, Wang Li, Ficarro Scott B, Buhrlage Sara, Wu Hao, Marto Jarrod A, Treon Steven P, Gray Nathanael S
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States.
Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Longwood Center LC-2209, Boston, Massachusetts 02115, United States.
ACS Med Chem Lett. 2020 Oct 9;11(11):2238-2243. doi: 10.1021/acsmedchemlett.0c00378. eCollection 2020 Nov 12.
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.
白细胞介素1（IL-1）受体相关激酶（IRAKs）是丝氨酸/苏氨酸激酶，在启动针对外来病原体的先天免疫反应中起关键作用。此外，IRAK1信号失调在肿瘤性疾病中起作用。例如，IRAK1被证明对许多B细胞淋巴瘤的存活和增殖很重要，包括华氏巨球蛋白血症（WM）和ABC亚型弥漫性大B细胞淋巴瘤（DLBCL）细胞。在此，我们报告了一种高效且选择性的IRAK1共价抑制剂JH-X-119-01的发现。完整蛋白质MS标记研究证实JH-X-119-01在C302处不可逆地标记IRAK1。该化合物在一组WM、DLBCL和表达MYD88的淋巴瘤细胞系中以个位数微摩尔浓度表现出细胞毒性活性。JH-X-119-01与BTK抑制剂依鲁替尼联合处理在这些系统中产生协同杀伤作用。综上所述，JH-X-119-01代表了一种用于进一步开发的高度选择性的IRAK1探针。
