1,3-Thioureas as First In Class Mitochondrial Inhibitors to Treat Oral Cancer

Abstract Keraceuticals is developing a patent-protected novel class of anticancer drugs called 1,3-thioureas for the treatment of oral squamous cell carcinoma (OSCC). OSCC is the most common oral malignancy, accounting for 80–90% of all oral cancers and 60% of all cases of head and neck squamous cell carcinoma (HNSCC). Among

all types of HNSCC, OSCC has the highest recurrence rates and lowest median survival. Even with additional treatment, the survival rate for recurrent OSCC is a mere 6-7 months. Patient outcomes for OSCC have not changed in 50-years, due in part to the fact that no targeted therapies have been developed for advanced and

recurrent OSCC. Thus, there is a significant unmet need to identify and develop novel therapies to treat OSCC. In response to this need, Keraceuticals developed 1,3-thioureas that demonstrate potent antiproliferative effects against a panel of cancer types including OSCC, non-small cell lung cancer, breast, prostate, brain, and

endometrial cancer in vitro. 1,3-thioureas inhibit oxidative phosphorylation (OXPHOS) and calcium homeostasis in cancers providing a one-two punch that results in endoplasmic reticulum stress, mitochondrial membrane depolarization, and subsequent reactive oxygen species-driven apoptosis selectively in tumor cells.

Keraceuticals’ lead compound, CIDD99 has shown promising results in OSCC cell lines, and significantly reduced tumor volumes (5-fold) in OSCC mouse xenograft models when administered intraperitoneally. However, additional R&D is required to develop formulations for oral and/or intravenous administration of

CIDD99 and to determine the bioavailability of subsequent PK and tissue distribution prior to initiating manufacturing, full-scale toxicology studies, and clinical trials. This Phase I project proposes the following Aims: 1. Formulate CIDD99 for oral and/or IV administration. Rapid assessment of these oral and/or IV formulations

will be performed on blood from non-tumor-bearing mice and enable fast identification of appropriate formulations for larger efficacy studies, comprehensive PK studies, and tissue distribution analyses. Formulations with equal or improved blood concentrations will be utilized in Aim 2. 2. Confirm formulated CIDD99 efficacy and compare

against standards of care in mouse OSCC models. The most efficacious formulation will be evaluated as a lone treatment or in combination with cisplatin or the epidermal growth factor receptor (EGFR) inhibitors cetuximab and gefitinib. Lastly, tongue tumor models will be used to assess metastatic disease. Effects on tumor growth,

nodal disease, tolerability, tissue distribution, and histopathology will be assessed, and initial toxicity analyses will be performed. These key studies will verify efficacy of formulations that enable oral and/or IV administration for future clinical trials. Mechanistic effects on in vivo EGFR signaling, apoptosis, and markers of epithelial

mesenchymal transition will also be evaluated. The above studies and proposed milestones will serve as Go/No Go criteria for a future Phase II application that will confirm efficacy in additional mouse models and initiate GMP manufacturing as well as IND-enabling toxicology studies in preparation for IND submission.