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.

Automated summary

PROTACs have emerged as an innovative drug development platform with the potential to target specific proteins for degradation. Computational modeling has revealed that the accessibility of lysines on a target protein plays a crucial role in determining the selectivity and potency of PROTACs. The development of a dual degrader targeting BCL-xL and BCL-2 shows significantly improved antitumor activity, highlighting the importance of understanding target protein structure in PROTAC design.