Dongwen Lv, Pratik Pal, Xingui Liu, Yannan Jia, Dinesh Thummuri, Peiyi Zhang, Wanyi Hu, Jing Pei, Qi Zhang, Shuo Zhou, Sajid Khan, Xuan Zhang, Nan Hua, Qingping Yang, Sebastian Arango, Weizhou Zhang, Digant Nayak, Shaun K Olsen, Susan T Weintraub, Robert Hromas, Marina Konopleva, Yaxia Yuan, Guangrong Zheng, Daohong Zhou
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引用次数: 44
摘要
靶向蛋白水解嵌合体(PROteolysis-TArgeting Chimeras, PROTACs)已成为一种创新的药物开发平台。然而，大多数PROTAC是经验性生成的，因为许多决定PROTAC特异性和活性的因素仍然难以捉摸。通过对整个NEDD8-VHL Cullin RING E3泛素连接酶(CRLVHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1复合物的计算建模，我们发现该复合物只能泛素化BCL-xL上特定波段区域的赖氨酸。利用这种方法指导我们开发一系列abt263衍生和vhl招募的PROTACs，我们产生了一种有效的BCL-xL和BCL-2 (BCL-xL/2)双重降解剂，具有显著提高抗BCL-xL/2依赖性白血病细胞的抗肿瘤活性。我们的研究结果提供了实验证据，表明赖氨酸在靶蛋白上的可及性在决定PROTAC诱导蛋白质降解的选择性和效力方面起着重要作用，这可能为指导PROTAC的未来发展提供一个概念框架。
Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity.
PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRLVHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.
期刊介绍：
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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