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Anti-apoptotic protein BCL-X_L plays a key role in tumorigenesis and cancer chemotherapy resistance, rendering it an attractive target for cancer treatment. However, BCL-X_L inhibitors such as ABT-263 cannot be safely used in the clinic because platelets solely depend on BCL-X_L to maintain their viability. To reduce the on-target platelet toxicity associated with the inhibition of BCL-X_L, we designed and synthesized PROTAC BCL-X_L degraders that recruit CRBN or VHL E3 ligase because both of these enzymes are poorly expressed in human platelets compared to various cancer cell lines. We confirmed that platelet-toxic BCL-X_L/2 dual inhibitor ABT-263 can be converted into platelet-sparing CRBN/VHL-based BCL-X_L specific degraders. A number of BCL-X_L degraders are more potent in killing cancer cells than their parent compound ABT-263. Specifically, XZ739, a CRBN-dependent BCL-X_L degrader, is 20-fold …