Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Nat Commun. 2021 Nov 25;12(1):6896. doi: 10.1038/s41467-021-27210-x.
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 (CRL)/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.
蛋白水解靶向嵌合体（PROTACs）已经成为一种创新的药物开发平台。然而，由于许多决定 PROTAC 特异性和活性的因素仍然难以捉摸，因此大多数 PROTAC 都是通过经验产生的。通过对整个 NEDD8-VHL Cullin RING E3 泛素连接酶（CRL）/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 上一个定义的带区域的赖氨酸。我们使用这种方法来指导我们开发一系列基于 ABT263 和 VHL 招募的 PROTAC，生成了一种有效的 BCL-xL 和 BCL-2（BCL-xL/2）双重降解剂，对依赖 BCL-xL/2 的白血病细胞具有显著提高的抗肿瘤活性。我们的结果提供了实验证据，表明靶蛋白上赖氨酸的可及性在决定 PROTAC 诱导蛋白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。
