Liu Jiyuan, Tian Zhen, Zhou Nan, Liu Xueying, Liao Chenyi, Lei Beilei, Li Jianing, Zhang Shengyong, Chen Hui
Department of Medicinal Chemistry, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, Shaanxi, China.
Northwest A&F University, Yangling, 712100, Shaanxi, China.
Oncotarget. 2017 Apr 20;8(33):54236-54242. doi: 10.18632/oncotarget.17294. eCollection 2017 Aug 15.
Despite intensive efforts in the search for small molecules with anti-cancer activity, it remains challenging to achieve both high effectiveness and safety, since many agents lack the selectivity to only act on cancer cells. The interface of two apoptotic proteins, myeloid cell leukemia-1 (Mcl-1) and p53 upregulated modulator of apoptosis (PUMA), has been recently affirmed as a target for treating cancers, as the disruption of Mcl-1-PUMA binding can reduce cancer cell survival and protect normal cells from apoptosis. However, therapeutic agents that target this interface are yet to be found. In this work, we combined pharmacophore modelling and biological tests to seek small molecules which target the Mcl-1-PUMA interface. For the first time, a small-molecule compound was identified. Its dual activity has been validated to reduce PUMA-dependent apoptosis while deactivating Mcl-1-mediated anti-apoptosis in cancer cells. Our results would provide a new avenue for the development of effective and safe anti-cancer agents.
尽管在寻找具有抗癌活性的小分子方面付出了巨大努力，但要实现高效性和安全性仍然具有挑战性，因为许多药物缺乏仅作用于癌细胞的选择性。髓样细胞白血病-1（Mcl-1）和p53上调凋亡调节因子（PUMA）这两种凋亡蛋白的界面最近已被确认为治疗癌症的靶点，因为破坏Mcl-1-PUMA结合可降低癌细胞存活率并保护正常细胞免于凋亡。然而，尚未找到靶向该界面的治疗药物。在这项工作中，我们结合药效团建模和生物学测试来寻找靶向Mcl-1-PUMA界面的小分子。首次鉴定出一种小分子化合物。其双重活性已得到验证，可减少PUMA依赖性凋亡，同时使癌细胞中Mcl-1介导的抗凋亡失活。我们的结果将为开发有效且安全的抗癌药物提供一条新途径。
