PZ18753B

PZ18753B is a dual Bcl-xL and Bcl-2 proteolysis-targeting chimera (PROTAC) degrader designed to overcome resistance to Bcl-2 inhibitors like venetoclax in chronic lymphocytic leukemia (CLL). It is derived from the dual Bcl-2/Bcl-xL inhibitor navitoclax, conjugated to a ligand for the Von Hippel-Lindau (VHL) E3 ligase. By recruiting VHL, PZ18753B induces the ubiquitination and subsequent proteasomal degradation of both Bcl-xL and Bcl-2. This approach aims to exploit the differential expression of VHL in cancer cells versus platelets to minimize the thrombocytopenia typically associated with direct Bcl-xL inhibition. Preclinical studies demonstrate that PZ18753B is highly potent against venetoclax-resistant CLL cells, including those with Bcl-2 mutations (e.g., G101V) where it retains the ability to degrade Bcl-xL even if the mutant Bcl-2 is not degraded.