Design and Evaluation of Small Molecules That Target the Dimerization Interface of Full-Length and Splice-Variant Forms of the Androgen Receptor
[Technical Report, Annual Report]
UNIVERSITY OF BRITISH COLUMBIAVANCOUVER PROSTATE CENTREUNIVERSITY OF MINNESOTA
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The main factor required for all stages of prostate cancer PCa development and progression is the androgen receptor AR, a molecular signaling protein resident within prostate cancer cells that is switched on by testosterone, which in turn interacts with DNA to orchestrate a genetic program that promotes the growth of PCa cells. The major problem for PCa patients is that these therapeutic approaches invariably fail because the testosterone binding site on the AR protein becomes mutated. These mutations often switch the AR protein on permanently without the normal signal from testosterone,enabling it to continue interacting with DNA and orchestrating the genetic program that promotes the growth of prostate cancer cells. We will develop a completely new series of novel drug-like small molecules that target another essential function that we recently elucidated for mutated AR proteins. This process is known as dimerization, whereby two mutated AR proteins must physically bind to each other to interact with DNA and orchestrate the genetic program that promotes growth of PCa cells. Here, we aim to interfere with this dimerization process by developing a drug-like small molecule that functions as an anti-dimer therapy. We hypothesize that anti-dimer drugs will be effective for treating PCas that contain mutant forms of AR that underlie resistance to conventional therapies.
- Medicine and Medical Research