Targeting MCL-1 with APG-3526: Unveiling a Potent Inhibitor for Cancer Therapy

The research focuses on MCL-1, a protein that prevents cell death in various cancers, including prostate, lung, and breast. This protein is often overexpressed and contributes to resistance to common treatments. The study introduces APG-3526, a new compound that has shown significant antitumor effects in vitro and in vivo.

APG-3526 was synthesized through a multistep process and its binding to MCL-1 was measured using a fluorescence polarization assay. The compound's impact on cell viability was assessed with the CCK-8 assay, and its antitumor efficacy was tested in multiple myeloma xenograft models in mice.

The results indicate that APG-3526 has a high affinity for MCL-1 and is effective in inhibiting the growth of MCL-1-dependent cancer cells. Treatment with APG-3526 led to complete tumor regression in the tested models. Pharmacodynamic studies showed that the compound induced apoptosis by activating caspase 3 and cleaving PARP. Furthermore, APG-3526 was found to disrupt the MCL-1:BIM complex, initiating the apoptotic process.

In summary, APG-3526 is a novel and potent MCL-1 inhibitor with favorable pharmacokinetic properties, demonstrating strong antiproliferative and antitumor activities. The compound is considered a promising candidate for further clinical development as an MCL-1 inhibitor.