PROTAC is an emerging therapeutic modality. PROTAC is a feasible solution to reduce platelet toxicity associated with BCL-XL inhibition. BCL-XL plays a key role in tumorigenesis and cancer chemotherapy resistance. As a result, BCL-XL is an attractive target for cancer treatment. Specifically, XZ739 is a CRBN-dependent BCL-XL degrader.

XZ739, which contains a PEG linker with linker length of 11 atoms, is a potent BCL-XL degrader against MOLT-4 cells. Especially, XZ739 treatment leads to remarkable BCL-XL degradation with a DC50 at 2.5 nM. XZ739 exhibits 100-fold selectivity for MOLT-4 cells over human platelets, whereas ABT-263 has no selectivity. Western blot analysis reveals that XZ739 dose-dependently induces BCL-XL degradation in MOLT-4 cells. In addition, XZ739 rapidly induces the BCL-XL degradation in MOLT-4, starting within 2 h; and 8 h after XZ739 treatment, more than 96% of the protein is degraded with 100 nM of XZ739.

The effects of XZ739 on BCL-XL protein levels in MOLT-4 are long-lasting and also reversible. Further, proteasome inhibitor MG-132 or excess competitive CRBN ligand Pomalidomide can abrogate XZ739-induced BCL-XL degradation. 10 nM of XZ739 treatment for 48 h significantly increases the percentage of Annexin-V-positive cells in MOLT-4 cells compared to the vehicle group. In addition, pretreatment with 10 μM of pan-caspase inhibitor Q-VD-OPh (QVD) for 2 h partially inhibited the XZ739-induced apoptosis, which confirms that XZ739 induces cell death through a caspase-dependent mechanism. The mouse plasma stability assay and preliminary pharmacokinetic study reveals that XZ739 is bioavailable.

Overall, XZ739, a CRBN-based BCL-XL PROTAC, is potent against various cancer cell lines.

Xuan Zhang , et al. Discovery of PROTAC BCL-X L Degraders as Potent Anticancer Agents With Low On-Target Platelet Toxicity. Eur J Med Chem. 2020 Apr 15;192:112186.