Discovery of XZ338, a highly potent BCL-XL degrader.

BCL-XL is a crucial anti-apoptotic protein involved in tumorigenesis and resistance to cancer chemotherapy. Transitioning from conventional inhibitors to PROTAC degraders has shown promising potential, particularly in minimizing the on-target thrombocytopenia linked to BCL-XL inhibition. However, reported BCL-XL degraders were mostly derived from BCL-XL/BCL-2 dual inhibitor ABT-263, which also inhibits or degrades BCL-2 and can potentially cause neutropenia when combined with conventional chemotherapy as seen with ABT-263 in the clinic. The goal of the present study is to develop a highly specific BCL-XL degrader without BCL-2 inhibition/degradation. In this study, XZ338, a highly potent and selective BCL-XL degrader derived from BCL-XL specific inhibitor A-1331852, was generated. XZ338 is 70-fold more potent than ABT-263 against MOLT-4 T-ALL cells, with over 89-fold selectivity for MOLT-4 cells over human platelets.