State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Lung Cancer Center, Laboratory of Lung Cancer, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Bioorg Chem. 2021 May;110:104820. doi: 10.1016/j.bioorg.2021.104820. Epub 2021 Mar 10.
Human caseinolytic protease proteolytic subunit (HsClpP) is a highly conserved serine protease that plays an essential role in cell homeostasis through removal of the damaged and/or misfolded proteins. Recently, due to its critical role in cancer proliferation and metastasis, HsClpP has been considered as a promising target for the cancer treatment. In this paper, through a random screening toward a library of 2086 bioactive chemicals, a novel compound I, 3-(3,5-dibromo-4-hydroxybenzylidene) -5-iodoindolin-2-one, was identified as a potent suppressor of HsClpP. Herein, a series of compound I derivatives were synthesized, and evaluated for their anti-cancer activities on a variety of cancers cells. Through the preliminary biological assay in vitro, including MTT assay and proteolytic activity assay, compound I was identified as the most potent inhibitor. Treatment with compound I impaired the migration of Hela cells. In addition, compound I disrupted the mitochondrial function, and reduced the level of the SDHB and induced the production of the ATF4. In general, compound I is a promising probe of HsClpP for cancer treatment, and is a good lead compound for the development of novel anti-cancer agent.
人组织蛋白酶 L 蛋白酶体水解亚基 (HsClpP) 是一种高度保守的丝氨酸蛋白酶，通过去除受损和/或错误折叠的蛋白质，在细胞内稳态中发挥着重要作用。最近，由于其在癌症增殖和转移中的关键作用，HsClpP 已被认为是癌症治疗的有前途的靶点。在本文中，通过对 2086 种生物活性化合物文库的随机筛选，鉴定出一种新型化合物 I，3-(3,5-二溴-4-羟基苯亚甲基)-5-碘吲哚啉-2-酮，作为 HsClpP 的有效抑制剂。在此，合成了一系列化合物 I 的衍生物，并对其在多种癌症细胞中的抗癌活性进行了评价。通过体外初步生物学测定，包括 MTT 测定和蛋白水解活性测定，发现化合物 I 是最有效的抑制剂。用化合物 I 处理会损害 Hela 细胞的迁移。此外，化合物 I 破坏了线粒体功能，降低了 SDHB 的水平，并诱导了 ATF4 的产生。总的来说，化合物 I 是一种有前途的 HsClpP 探针，可用于癌症治疗，也是开发新型抗癌药物的良好先导化合物。
