Design and Evaluation of Small Molecules That Target the Dimerization Interface of Full-Length and Splice-Variant Forms of the Androgen Receptor

Androgen Receptor (AR) in Prostate Cancer: Prostate cancer continues to be a leading cause of death for men in North America. The main factor required for all stages of prostate cancer development and progression is the AR, a molecular signaling protein resident within prostate cancer cells that is switched on by male sex steroid hormones, such testosterone. When the AR protein is switched on by testosterone, it interacts with DNA to orchestrate a genetic program that promotes the growth of prostate cancer cells.

The Problem – Prostate Cancer Therapeutic Resistance: Conventional prostate cancer therapies exploit this hormone requirement of prostate cancer cells by targeting the specific site on the AR protein that physically binds testosterone. The major problem for prostate cancer patients is that these therapeutic approaches invariably fail because this testosterone binding site on the AR protein becomes mutated. These mutations often switch the AR protein on permanently without the normal signal from testosterone, allowing it to continue interacting with DNA and orchestrating the genetic program that promotes the growth of prostate cancer cells.

Our Approach to Overcome Therapeutic Resistance: The development of small molecules that attack the molecular functions of the androgen receptor, distinct from testosterone binding, is hence a novel area of investigation to inhibit these mutated forms of the AR and overcome resistance to conventional treatments. Our laboratories at the University of British Columbia and University of Minnesota have collaborated in the past to create drug prototypes that compromise the necessary DNA interacting function of the AR protein. Our collaboration advanced these prototypes to a stage where they were licensed and are now being developed under a historic drug development partnership between the University of British Columbia and industry. In the present proposal, this proven strategy will be applied to 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 essential function is a process 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 prostate cancer 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 prostate cancers that contain mutant forms of AR that underlie resistance to conventional therapies. Thus, our pioneering work has the potential to yield new therapies that target essential functions of mutant AR proteins and thereby improve survival and quality of life of prostate cancer patients.