Zuo Haojie, Ru Yiming, Gao Xiuxiu, Chen Hui, Yan Yaoyao, Ma Xiaodong, Liu Xinhua, Wang Yang
School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China.
Department of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei 230012, China.
ACS Med Chem Lett. 2024 Jul 29;15(8):1205-1212. doi: 10.1021/acsmedchemlett.4c00310. eCollection 2024 Aug 8.
The vast majority of tumor cells maintain the length of the telomeres through a telomerase-dependent maintenance mechanism, allowing for unlimited proliferation. TCAB1 is indispensable for the correct assembly of telomerase complexes and the delivery of telomerase to the telomere. Therefore, this study aimed to explore small molecules capable of interfering with the assembly of TCAB1 and the telomerase complex as novel efficient telomerase inhibitors. Through virtual screening, biological evaluation, and the confirmation of target engagement, the potential ligands of TCAB1 effectively inhibiting telomerase activity were discovered. Among them, compound exhibited telomerase inhibitory activity at a two-digit nanomolar level (IC = 0.03 μM), which was dramatically enhanced in comparison with the previously reported telomerase inhibitors. This research, based on the blockage of telomerase assembly through disturbing TCAB1, provides a novel strategy and a potential target for telomerase inhibitor discovery.
绝大多数肿瘤细胞通过端粒酶依赖性维持机制维持端粒长度，从而实现无限增殖。TCAB1对于端粒酶复合物的正确组装以及端粒酶向端粒的递送是不可或缺的。因此，本研究旨在探索能够干扰TCAB1与端粒酶复合物组装的小分子，作为新型高效的端粒酶抑制剂。通过虚拟筛选、生物学评价以及靶点结合确认，发现了有效抑制端粒酶活性的TCAB1潜在配体。其中，化合物在两位数纳摩尔水平表现出端粒酶抑制活性（IC = 0.03 μM），与先前报道的端粒酶抑制剂相比有显著增强。本研究基于通过干扰TCAB1来阻断端粒酶组装，为端粒酶抑制剂的发现提供了一种新策略和潜在靶点。
