PROTACs are effective in addressing the platelet toxicity associated with BCL-X_L inhibitors

BCL-X_L is an anti-apoptotic protein that plays an important role in tumorigenesis, metastasis, and intrinsic or therapy-induced cancer drug resistance. More recently, BCL-X_L has also been identified as a key survival factor in senescent cells. Accumulation of senescent cells has been indicated as a causal factor of aging and many age-related diseases and contributes to tumor relapse and metastasis. Thus, inhibition of BCL-X_L is an attractive strategy for the treatment of cancer and extension of healthspan. However, development of BCL-X_L inhibitors such as navitoclax for clinical use has been challenging because human platelets depend on BCL-X_L for survival. In this review, we discuss how BCL-X_L-targeted proteolysis targeting chimeras (PROTACs) afford a novel approach to mitigate the on-target thrombocytopenia associated with BCL-X_L inhibition. We summarize the progress in the development of BCL-X_L PROTACs. We highlight the in vitro and in vivo data supporting that by hijacking the ubiquitin protein ligase (E3) that are poorly expressed in human platelets, BCL-X_L PROTACs can significantly improve the therapeutic window compared to conventional BCL-X_L inhibitors. These findings demonstrated the potentially broad utility of PROTAC technology to achieve tissue selectivity through recruiting differentially expressed E3 ligases and to reduce on-target toxicity.