Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer
Abstract
Androgens are hormones that play a critical role in stimulating prostate cancer growth. Androgens activate a protein called the androgen receptor (AR), which regulates genes involved in cell growth. Although powerful anti-androgen drugs can be administered to block AR action and have been used successfully to treat patients with prostate cancer, over time the tumors become resistant to the drugs, leaving few treatment options. The goal of this proposal is to develop a new approach to block AR activity and stop prostate cancer growth using a new family of molecules called multivalent peptidomimetic conjugates. Peptidomimetic oligomers are chain-like molecules that resemble a small protein. Our previous published studies show that we can synthesize complex peptidomimetics that present a precise array of multiple anti-androgen groups along the molecular chain. This is an important advantage because having a united array of multiple anti-androgens may improve binding to AR, allowing these molecules to block the ability of the receptor protein to fuel cancer growth. Our ongoing studies show that our compounds can alter the structure of hormone receptors in unprecedented ways, potentially leading to a new family of drug molecules. Preliminary results show they can potently check the growth of cells derived from late-stage prostate cancer and that they can slow the growth of tumors in animal models of the disease. To accomplish our goals, we will create a set of conjugates with anti-androgens linked to the peptidomimetic backbone at variable intervals along the molecular chain. We will test these molecules for their ability to bind to AR. Those that bind tightly will then be tested in tumor models to evaluate if they block androgen-dependent prostate cancer cell growth. To understand how these molecules block AR function, we will determine the three-dimensional structure of AR bound to the peptidomimetic conjugates. These studies will be used to guide our ability to tailor the conjugates for optimal interactions with the AR. Our approach to drug discovery will partner our innovations in the chemical synthesis of multivalent antiandrogen displays, in combination with our experience in studying the activity of hormone receptors. This synergy will allow us to discover new therapies to combat late-stage prostate cancer. Applicability of the Research: What types of patients will this help? This research will help patients with castration-resistant prostate cancer that is refractory to standard treatments. What are the potential clinical applications? Clinicians will gain a powerful tool in their armamentarium to treat prostate cancer in its most lethal phases. The mechanism of action of these molecules may avert rapid development of resistance and additional tumor growth. Our goal is to alleviate suffering and extend lifespan for patients with poor treatment options. Will the study achieve a patient-related outcome? This is a preclinical study that will pave the way for a future clinical trial. It will achieve a patient-related outcome by laying the groundwork for moving these innovative molecules into the clinic. Because our preliminary study has already indicated safety and efficacy in animal models of disease, and because of our ability to efficiently synthesize variations of these compounds, it may prove possible to move quickly into clinical evaluations to benefit patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510589
Entities
People
- Kent Kirshenbaum
Organizations
- New York University
- United States Army