BACKGROUND
Advanced stage malignant ovarian cancer (MOC) is an incurable disease of women, resistant to chemotherapies with agents such as cisplatin, carboplatin and taxane. MOC chemotherapies also have limited tumor specificity and cause significant toxicity, resulting in modest efficacy and recurrence in greater than 70% of treated patients. Thus, there is a critical need to overcome the conventional chemotherapy barriers, and develop new means to treat and prevent recurrence of ovarian cancers, while minimizing adverse side effects to patients.
Our group’s previous discovery and extensive research of SHetA2 (US patent No.: 6,586,460 B) have led to discovery of SHetA2’s binding to mortalin (mitochondrial heat shock protein 70). Having gained recognition as a useful agent in the treatment of a variety of cancers SHetA2 belongs to a family of heterocyclic compounds and exhibits growth inhibition on 60 cancer cell lines in vitro, and in ovarian, NSCLC (lung cancer), and kidney cancers in vivo.
SUMMARY OF TECHNOLOGY
SHetA2 induces both intrinsic (mitochondrial mediated) and extrinsic (death receptor mediated) apoptosis pathways in cancer cells. This agent exhibited discriminatory activity against malignant cells versus normal cells and demonstrates very low toxicity in rats and dogs.
Using solution NMR structure and predictions from our molecular modeling studies, we synthesized new compounds that exhibited enhanced binding affinity to a target protein, and increased efficacy against ovarian cancer cells. A number of new compounds outperformed SHetA2 in the inhibition of human ovarian cancer cells, and demonstrated improved IC50 = 2 to 2.5 mM).
Efficacy and toxicity of the compounds in a mouse model of ovarian cancer is currently being evaluated. However, based on researcher’s knowledge of structure activity relationships, it is likely that new compounds will exhibit anticancer efficacy with a wide therapeutic window. The new compounds are expected to have activity in cells with both wild type and mutant p53 status.
POTENTIAL AREAS OF APPLICATION
- New single agent for >3rd line or refractory ovarian cancer patients
- The compound can be used in combination treatment with first- and second-line chemotherapy
MAIN ADVANTAGES
- Increased efficacy against ovarian cancer cells (IC50 = 2 to 2.5 mM)
- New mechanism of action involving a heat shock protein 70. Current drug development pipeline for ovarian cancer is dominated by PARP, angiogenesis and PD-L1 inhibitors. To our knowledge, MKT-077 was the only drug, evaluated in the clinical setting, that has a similar mechanism of action
- Expected enhanced bioavailability of our new analogues will facilitate oral formulation development
- Prior art search confirmed novelty of our compounds allowing composition of matter intellectual property protection
COMMERCIAL OPPORTUNITY
According to GlobalData, ovarian cancer market is expected to reach $5.2 billion by 2025. Ovarian cancer is a condition with high unmet medical need since approximately two-thirds of woman are diagnosed when the ovarian cancer is at an advanced stage, when the five-year survival rate is less than 50%. Worldwide over 230,000 new ovarian cancer cases are diagnosed each year and 140,000 women die from this cancer. Due to limited success in treating late stage or drug resistant ovarian cancers there is a critical need for developing new anticancer drugs and drug combinations for this debilitating disease. We are looking for partners to help us with additional optimization of our lead compound in terms of efficacy and aqueous solubility.
STAGE OF DEVELOPMENT