42P - A promising anticancer drug for triple-negative breast cancer: OZ-001 suppresses tumor growth by dual targeting STAT3 and calcium signaling

Background

The study investigates the potential of OZ-001, a novel 3,4-dihydroquinazoline derivative containing a ureido group, against diverse cancers. Conventional chemotherapy has limited impact on triple-negative breast cancer (TNBC), and targeted TNBC therapies are lacking. OZ-001 is expected to target both signal transducer and activator of transcription 3 (STAT3) inhibition and T-type calcium channel blocking simultaneously.

Methods

The efficacy and potency of OZ-001 were assessed using MDA-MB-231 cells both in vitro and in vivo. Cell-based assays compassing cell viability, apoptosis, protein expression, cell cycle analysis, fluorescence polarization assay (FP), and intracellular calcium levels were conducted. An in vivo xenograft model using MB-231 cells gauged impact of OZ-001 via oral administration (ranging from 15 to 60mg/kg). Preliminary toxicity evaluation of OZ-001 was conducted using an in vivo model with RD rats.

Results

In vitro, OZ-001 displayed substantial does-dependent inhibition of cell viability inducing a remarkable 10-fold increase in apoptotic genes Bax and caspase-3 compared to the control. As a STAT3 inhibitor, OZ-001 effectively disrupted STAT3-STAT3 interactions in the FP assay, and it reduce STAT3 phosphorylation by 90%. As a T-type calcium channel blocker, OZ-001 exhibited the capability to reduce intracellular calcium levels by 50%, resulting in a notable 90% reduction in calcium signaling. In vivo, OZ-001 led to a 50% reduction in tumor size at a dose of 15mg/kg, and an impressive 95% at 60mg/kg (P.O.), compared to the vehicle-treated group, while a 70% reduction in tumor size at a dose of 10 mg/kg (IP) of Paclitaxel was observed. In a single oral dose toxicity evaluation using SD rats, no specific clinical sign or distinctive necropsy findings were observed, even at a dose of 2,000 mg/kg of OZ-001. This indicates its favorable safety profile.

Conclusions

OZ-001 emerges as a promising therapeutic candidate for TNBC, demonstrating exceptional efficacy as an orally active single agent in reducing tumor growth. The preclinical results present an encouraging avenue for further exploration and development of OZ-001 as a viable alternative for addressing TNBC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

ONCOZEN Co., Ltd.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.