Development of Small Molecule Activators of Protein Phosphatase 2A (SMAPs) for the Treatment of Castration-Resistant Prostate Cancer

Project Details

Description

We have taken a novel approach to the development of a new class of drugs to treat prostate cancer by first starting with the observation that the tricyclic neuroleptics, drugs that have been used to treat psychiatric conditions for over 60 years, have anticancer properties. In epidemiologic studies, patients with schizophrenia taking these drugs have a significantly lower likelihood of developing prostate cancer, and in laboratory studies, these drugs have been shown to kill prostate cancer cells. However, developing this class of drugs for the treatment of cancer has been limited by (1) 'central nervous system side effects' including lethargy, muscle spasms, and Parkinson's-like symptoms and (2) a lack of understanding regarding how these drugs exert their anticancer effects. Therefore, we have used these drugs as a starting point, and through medicinal chemistry, have created a new class of drugs that retain the anticancer effects of the tricyclic neuroleptics but lack the unfavorable central nervous system side effects.

We have now uncovered the mechanism by which these novel drugs exert anticancer effects -- by activating Protein Phosphatase 2A (PP2A). Phosphatases remove phosphate groups from other proteins, thereby deactivating those proteins akin to 'turning off a light switch.' PP2A is responsible for deactivating some of the key proteins that allow prostate cancer cells to grow, including the androgen receptor. Typically, PP2A does not function well in prostate cancer cells. By activating PP2A with a drug, this may coordinately turn off many of the proteins that cause prostate cancer cells to grow, thereby causing prostate cancer cell death. Indeed, we have shown this to be the case in the laboratory. These findings are critical in that (1) to our knowledge, this is the first clinically viable approach to activating a phosphatase for the treatment of cancer or any disease; (2) activating PP2A for the treatment of prostate cancer is a completely novel approach that may overcome resistance to currently available treatments; (3) the androgen receptor, the key therapeutic target in prostate cancer, is degraded by these novel drugs in the laboratory; and (4) our new class of drugs was developed by making conservative chemical modifications to existing medications that have been used safely in patients for decades, decreasing the likelihood that these drugs will fail in clinical development due to unanticipated toxicities.

The current proposal focuses on demonstrating that these novel drugs have anti-prostate cancer properties in more complex clinically relevant (mouse) models of prostate cancer and refining our understanding of the mechanism by which PP2A activation with these drugs causes prostate cancer cell death. The results of the outlined studies will position DT-1154, our lead drug candidate, for a near-term clinical trial in men with castration-resistant prostate cancer. Ultimately, PP2A-activating drugs have the potential to transform the treatment of prostate cancer and ease the pain and suffering of men with advanced disease.

StatusActive
Effective start/end date1/01/14 → …

Funding

  • Congressionally Directed Medical Research Programs: $251,502.00

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