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

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Daohong Zhou, M.D.

PROVIDER: MSV000094144 | MassIVE | Wed Feb 21 11:52:00 GMT 2024

SECONDARY ACCESSION(S): PXD050013

REPOSITORIES: MassIVE

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