OZ-001

Triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC) are aggressive malignancies characterized by uncontrolled tumor growth, high recurrence rates, and resistance to chemotherapy. OZ-001 is a small molecule with a dual mechanism of action targeting T-type Ca2+ channels and inhibiting activation of the signal transducer and activator of transcription 3 (STAT3) protein. These properties suggest a potential use as a therapeutic agent for TNBC and PDAC, addressing the urgent need for effective treatments. This study evaluates the anticancer efficacy and underlying mechanism of action of OZ-001. The anticancer activities of OZ-001 were assessed in MDA-MB-231 cells (against TNBC) and MIA PaCa-2 cells (against PDAC) through analyses of cell viability, apoptosis, protein characterization, and cell cycles. Protein affinity and intracellular calcium measurements were conducted to investigate its effects on STAT3 and T-type calcium channels. Xenograft animal models were developed using MDA-MB-231 and MIA PaCa-2 cells to evaluate the in vivo anticancer effects of OZ-001. We found that OZ-001 induced caspase-dependent MDA-MB-231 and MIA PaCa-2 cells by modulating Bcl-2 family proteins. It suppressed STAT3 phosphorylation, reducing the expression of survivin, Bcl-2, and cyclin D1. Specifically, OZ-001 blocked T-type calcium channels, which reduced intracellular calcium levels and activated apoptotic pathways. In vivo, oral administration of OZ-001 significantly reduced tumor growth in both xenograft models, likely due to diminished STAT3 phosphorylation and associated tumorigenic processes. These findings demonstrate the potential of OZ-001 to serve as an effective therapeutic agent for treating TNBC and PDAC.

We previously reported the anticancer activity of 4-(4-fluorobenzylcarbamoylmethyl)-3-(4-cyclohexylphenyl)-2-[3-(N,N-dimethylureido)-N'-methylpropylamino]-3,4-dihydroquinazoline (OZ-001), a T-type calcium channel (TTCC) blocker, against non-small cell lung cancer (NSCLC) in vitro and in vivo. Here, we evaluated the synergistic effect of OZ-001 and cisplatin on A549 human lung cancer cells and A549 xenograft mice. Our study demonstrated that treatment with OZ-001 and cisplatin sensitized A549 cells to cisplatin and significantly inhibited cell growth, increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, and induced poly (ADP-ribose) polymerase (PARP) cleavage in A549 cells and an A549 xenograft tumor mouse model. Moreover, our findings showed that mechanistic target of rapamycin (mTOR), ribosomal protein S6 kinase (p70S6K), and signal transducer and activator of transcription (STAT3) inactivation was required for apoptosis induced by the combination of OZ-001 and cisplatin in in vitro and in vivo experiments. Our results suggest that combined treatment with OZ-001 and cisplatin could potentiate antiproliferative effects via suppression of the mTOR/p70S6K and STAT3 pathways and may be considered a potential therapeutic agent for NSCLC.