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.

人酪蛋白水解蛋白酶蛋白水解亚基 (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稳态中发挥重要作用。最近，由于其在癌症增殖和转移中的关键作用，HsClpP 被认为是癌症治疗的有希望的靶点。在本文中，通过对 2086 种生物活性化学物质库的随机筛选，一种新型化合物I，3-(3,5-dibromo-4-hydroxybenzylidene) -5-iodoindolin-2-one，被鉴定为一种有效的抑制剂HsClpP。在此，合成了一系列化合物I衍生物，并评估了它们对多种癌细胞的抗癌活性。通过初步的体外生物学分析，包括MTT测定和蛋白水解活性测定，化合物I被鉴定为最有效的抑制剂。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是一种很有前景的 HsClpP 用于癌症治疗的探针，是开发新型抗癌药物的良好先导化合物。