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

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

Nature communications (2021-11-27)
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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Apyrase from potato, recombinant, expressed in Pichia pastoris, ATPase ≥1000 units/mg protein, lyophilized powder
Millipore
Anti-FLAG® M2 Magnetic Beads, affinity isolated antibody
Sigma-Aldrich
Q-VD-OPh hydrate, ≥95% (HPLC)
Sigma-Aldrich
Bcl-xL Active human, recombinant, expressed in E. coli, ≥90% (SDS-PAGE)
Sigma-Aldrich
Phenazine methosulfate
Sigma-Aldrich
Bcl-2 Active human, recombinant, expressed in E. coli, ≥80% (SDS-PAGE)