DT2216

DT2216 is a proteolysis-targeting chimera (PROTAC) based on the BH3-mimetic ABT263 which targets BCLXL to the Von Hippel-Lindau (VHL) E3 ligase for degradation. Unlike ABT263 (which functionally inhibits BCL2), DT2216 does not target BCL2 for degradation. Thus, relative to ABT263 it is a BCLXL selective compound. As BCLXL is an important determinant of platelet apoptosis, the clinical utility of ABT263 was limited by dose limiting yet on-target thrombocytopenia. As platelets have low VHL levels, dose limiting thrombocytopenia is not observed concurrent to clinically efficacious doses of DT2216. Thus, DT2216 represents a potent, cell active BCLXL-specific PROTAC which has anti-tumor activity in BCLXL-dependent tumors, without the toxicity of thrombocytopenia. This probe is highly specific for BCLXL and does not degrade other BCL2 family proteins. Much of the data presented in the initial description of this molecule was based on hematological cell lines (such as MOLT-4), but target degradation by this probe has also been verified in solid-organ cancer lines. Some caution needs to be exercised when determining dosage for in vitro cellular probing as the effective concentration range may vary and cells with low VHL (including platelets) will be resistant to the probe.