MassIVE MSV000094144

Partial Public PXD050013

Development and crystal structures of a more potent second-generation dual degrader of BCL-2 and BCL-xL

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Description

Overexpression of BCL-xL and BCL-2 play key roles in tumorigenesis and cancer drug resistance. Advances in PROTAC technology facilitated recent development of the first BCL-xL/BCL-2 dual degrader, 753b, a VHL-based degrader with improved potency and reduced toxicity compared to previous small molecule inhibitors. Here, we determined crystal structures of VHL/753b/BCL-xL and VHL/753b/ BCL-2 ternary complexes. The two ternary complexes exhibit markedly different architectures that are accompanied by distinct networks of interactions at the VHL/PZ753b-linker/target interfaces. The importance of these interfacial contacts was validated via functional analysis and informed subsequent rational and structure-guided design focused on the 753b linker and BCL-2/BCL-xL warhead. This resulted in the design of a novel degrader, WH244, with enhanced potency to degrade BCL-xL/BCL-2 in cells. Using biophysical assays followed by in cell activities, we were able to explain the enhanced target degradation of BCL-2/BCL-xL in cells. Most PROTACs are empirically designed and lack structural studies, making it challenging to understand their modes of action and specificity. Our work presents a streamlined approach that combines rational design and structure-based insights backed with cell-based studies to develop effective PROTAC-based cancer therapeutics. [doi:10.25345/C5SQ8QV19] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: PROTAC ; ubiquitin ; E3 ligase ; ternary complex ; BCL-xL/BCL-2 ; crystal structure ; degrader

Contact

Principal Investigators:
(in alphabetical order) 		Daohong Zhou, M.D., The University of Texas Health Science Center at San Antonio, U.S.A.
Submitting User: stweintraub
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