Description:
Project ID: TECH-2024-07
Background
Prostate cancer is one of the most common cancers and the second-most lethal cancer among men in the United States. While the response to standard androgen deprivation therapy (ADT) is often dramatic, most prostate cancer patients develop resistance to ADT, leading to castration-resistant prostate cancer (CRPC). Unfortunately, many patients with CRPC experience distant metastases, resulting in a median survival of about one year for these patients. Enzalutamide and docetaxel have emerged as first-line treatments for metastatic CRPC (mCRPC) in recent years. However, they only provide a modest increase in overall survival, extending it by a median of 4-5 months. Furthermore, a notable percentage of patients show no response to these medications, and resistance eventually develops in all patients. Thus, there is a critical unmet need to explore new strategies to improve outcomes and overall survival rates for individuals with mCRPC and patients with relapsed disease of other cancers.
Survivin (BIRC5) is a homo-dimeric protein of 16.5-kDa containing a single Baculovirus IAP Repeat (BIR) domain, a zinc-finger fold, and an extended C-terminal helical coiled coil, and is a member of the inhibitor of apoptosis protein (IAP) family that is expressed only in cancer cells but not in adult normal tissues. It functions majorly to inhibit apoptosis by deactivating caspases via coordinating with other IAPs. such as X-linked IAP (XIAP) and cellular IAP1/2 (c-IAP1/2). Survivin is up-regulated in most cancers including prostate cancer, but is absent in most adult normal tissues. Thus, Survivin has been considered an ideal target for cancer drug discovery. However, survivin is also considered an “undruggable” target because it lacks enzymatic activity or a proper binding pocket for small molecular inhibitors. Thus, both pharmaceutical companies and academic laboratories have been targeting upstream regulators of its expression, not the protein itself, leading to the discovery of YM155 and Terameprocol, which have been tested in clinical trials. However, this strategy has not worked due to a variety of reasons including a lack of specificity of the upstream target and the upstream regulators having too many downstream target genes. There remains a need in the art for compositions and methods for superior inhibition of survivin.
Invention Description
Researchers at the University of Toledo have developed a novel approach to target the homo-dimerization interface of Survivin to induce its degradation and identified inhibitors that inhibited tumor growth in animal models as a result of survivin inhibition. These optimized survivin inhibitors with new composition of matter targeting the dimeric interface of survivin are positioned for development of novel survivin-targeting cancer therapeutics.
Applications
- Novel class of potent Survivin degraders/inhibitors that can be used in combination with other compounds as targeted cancer treatments.
Advantages
- Targets survivin protein directly making side effects from other proteins less likely.
- New composition of matter is effective in suppressing tumor growth without apparent toxicity.
- Survivin degraders synergistic in combination with docetaxel, which is a commonly used anticancer drug, both in cell lines and animal models.
- Fairly easy to make with one-step chemical synthesis
IP Status: Patent Pending w/ USPTO