Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity

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 () and Daohong Zhou ()
Additional contact information
Dongwen Lv: College of Pharmacy, University of Florida
Pratik Pal: College of Pharmacy, University of Florida
Xingui Liu: College of Pharmacy, University of Florida
Yannan Jia: University of Texas M.D. Anderson Cancer Center
Dinesh Thummuri: College of Pharmacy, University of Florida
Peiyi Zhang: College of Pharmacy, University of Florida
Wanyi Hu: College of Pharmacy, University of Florida
Jing Pei: College of Pharmacy, University of Florida
Qi Zhang: University of Texas M.D. Anderson Cancer Center
Shuo Zhou: College of Pharmacy, University of Florida
Sajid Khan: College of Pharmacy, University of Florida
Xuan Zhang: College of Pharmacy, University of Florida
Nan Hua: College of Pharmacy, University of Florida
Qingping Yang: College of Pharmacy, University of Florida
Sebastian Arango: College of Pharmacy, University of Florida
Weizhou Zhang: Immunology and Laboratory Medicine, College of Medicine, University of Florida
Digant Nayak: Long School of Medicine, University of Texas Health Science Center at San Antonio
Shaun K. Olsen: Long School of Medicine, University of Texas Health Science Center at San Antonio
Susan T. Weintraub: Long School of Medicine, University of Texas Health Science Center at San Antonio
Robert Hromas: Mays Cancer Center, the Long School of Medicine, University of Texas Health Science Center at San Antonio
Marina Konopleva: University of Texas M.D. Anderson Cancer Center
Yaxia Yuan: College of Pharmacy, University of Florida
Guangrong Zheng: College of Pharmacy, University of Florida
Daohong Zhou: College of Pharmacy, University of Florida

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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 (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.

Date: 2021
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DOI: 10.1038/s41467-021-27210-x

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