Discovery and exploratory profiling of a novel BCL-XL PROTAC

Background BCL-XL is a key anti-apoptotic protein frequently overexpressed in various malignancies, where it contributes to therapy resistance. PROTAC technology offers a potential strategy to expand the therapeutic window by selectively degrading BCL-XL in tumor cells while sparing platelets. Herein, we present selected insights into the research and development of a novel BCL-XL PROTAC. Objectives This study aimed to characterize a CRBN-recruiting BCL-XL PROTAC series and identify key preclinical optimization considerations for BCL-XL degradation. Methods CRBN-based BCL-XL PROTACs were synthesized with medicinal chemistry methods and evaluated using MOLT-4 and RS4;11 cell viability assays, liver microsomal stability assays, mouse pharmacokinetic studies, BCL-XL degradation assays, platelet toxicity assays, and a MOLT-4 T-ALL xenograft model. Results A series of CRBN-based PROTACs achieved low-nanomolar cellular potency compared with the benchmark degrader DT2216. 25 exhibited potent BCL-XL degradation activity and reduced platelet toxicity. However, PK analysis revealed higher systemic clearance and lower plasma exposure. In a MOLT-4 xenograft model, 25 was well-tolerated but demonstrated limited tumor growth suppression. Conclusions This work established a proof-of-concept for CRBN-recruiting BCL-XL PROTACs as a platelet-sparing therapeutic strategy. Although 25 demonstrated superior in vitro potency, its in vivo antitumor efficacy was constrained by its suboptimal pharmacokinetic profile. This study serves as an exploratory framework for future optimization programs.