Year: 2021
Type: article
Abstract: 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 VHL )/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.
Source: Nature Communications
Authors: 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
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,560
Awards: G1183574029, Recruitment of Rising Stars, G204618756, G2172779025, G245889090, Develop BCL-xL proteolysis targeting chimeras as safer and better senolytics, G3060063492, EEPD1 Repair of Stressed Replication Forks, G3468900865, G4381593570, Obesity, inflammation and breast cancer, G4929638776, Structural Biology of the Ubiquitin Conjugation System, G5615350433, G6177109745, G6292026, CD177 suppresses breast-cancer development by inhibiting beta-catenin, G7532376268, Inhibition of Bcl-xL by Targeted Degradation, G7620602999, G8166109075, G9000034417, G9000101301, G9000151310, G9000278602, G9000296047, Structure and Function of the Essential Cell Cycle Regulator Cdc34, G941988676
OpenAlex ID: W3215130076