BCL-XL-targeting PROTACs

BCL-XL-targeting PROTACs (BCL-XL-Ps) are proteolysis-targeting chimeras designed to selectively degrade B-cell lymphoma extra-large (BCL-XL), an anti-apoptotic protein that plays a critical role in cancer cell survival, chemoresistance, and tumor-induced immunosuppression. By utilizing heterobifunctional small molecules that recruit an E3 ubiquitin ligase (such as VHL, CRBN, or IAPs) to BCL-XL, these degraders facilitate the polyubiquitination and subsequent proteasomal degradation of BCL-XL via the ubiquitin-proteasome system. This approach significantly reduces the on-target platelet toxicity (thrombocytopenia) associated with conventional small-molecule BCL-XL inhibitors like navitoclax, as platelets express very low levels of these E3 ligases. BCL-XL-Ps have demonstrated preclinical efficacy in reducing breast cancer metastasis, eliminating circulating tumor cells, and depleting tumor-infiltrating regulatory T cells (TI-Tregs) to enhance anti-tumor immunity.

Other names

BCL-XL-PsBcl-xl specific PROTACsBcl-xl-targeting proteolysis-targeting chimeras