Unveiling BCL-xL-specific PROTAC efficiency and dissociation pathways using native mass spectrometry.

ABSTRACT: Overexpression of anti-apoptotic proteins such as BCL-xL is a hallmark of various cancers and a major driver of resistance to conventional chemotherapies. While small-molecule BCL-xL inhibitors have shown promising outcomes, their clinical use is hindered by dose-limiting toxicities, especially thrombocytopenia. Proteolysis-targeting chimeras (PROTACs) offer a promising alternative by promoting selective degradation of target proteins via the ubiquitin-proteasome system, thereby reducing off-target effects associated with small molecule inhibitors. However, rational design and optimization of PROTACs remain challenging due to the need to balance simultaneous interactions with both an E3 ubiquitin ligase and the target protein. Here we employ native mass spectrometry (MS) as a rapid,

SUBMITTER: Gadallah MI 

PROVIDER: S-EPMC12917756 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature