Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
Leuk Lymphoma. 2019 Dec;60(12):2946-2950. doi: 10.1080/10428194.2019.1616190. Epub 2019 May 21.
With the advent of proteasome inhibitors (bortezomib) and pleiotropic pathway modulators which target cereblon E3 ligase (lenalidomide), the ubiquitin-proteasome system has emerged as a tractable target in non-Hodgkin lymphoma and multiple myeloma. Here we report that TAK-243, a small molecule inhibitor of the ubiquitin-activating enzyme (UAE), induced ER stress and the unfolded protein response in primary chronic lymphocytic leukemia cells, facilitating cell death. Moreover, targeting UAE was effective in ibrutinib-resistant mantle cell lymphoma cell lines and primary cells . Thus, UAE is a promising target in lymphoid malignancies, including ibrutinib-resistant lymphomas, an area of unmet medical need.
随着蛋白酶体抑制剂（硼替佐米）和多效途径调节剂（来那度胺）的出现，这些药物靶向 cereblon E3 连接酶，泛素-蛋白酶体系统已成为非霍奇金淋巴瘤和多发性骨髓瘤的一个可行的治疗靶点。在这里，我们报告称，小分子泛素激活酶（UAE）抑制剂 TAK-243 可诱导原发性慢性淋巴细胞白血病细胞中的内质网应激和未折叠蛋白反应，从而促进细胞死亡。此外，靶向 UAE 在伊布替尼耐药套细胞淋巴瘤细胞系和原代细胞中也有效。因此，UAE 是包括伊布替尼耐药淋巴瘤在内的淋巴恶性肿瘤的一个很有前途的治疗靶点，而伊布替尼耐药淋巴瘤正是目前尚未满足的医疗需求领域。
