Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy Resistant Prostate Cancer
The Scripps Research Institute Jupiter United States
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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 tumorsbecome 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. 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.