The overarching goal of this project is to bring a lead compound that targets the androgen receptor (AR) N-terminal domain to early phase clinical trials with the long-term goal of bringing a drug to regulatory approval that prolongs life expectancy and improves the quality of life of patients with the metastatic castration resistant prostate cancer (mCRPC), the stage and state of prostate cancer that accounts for virtually all prostate cancer-specific mortality. Thus, the key focus of this project is drug discovery and development. Several years of preclinical studies and subsequent proof-of-principle clinic trials established a pathophysiologic role for the AR in the emergence of CRPC. Unfortunately, primary or secondary resistance to all currently available drugs emerges in all patients. Thus, there is an unmet clinical need to develop effective therapies that can be applied as single agents in the post-abiraterone/post-enzalutamide setting and potentially in combination with current secondary generation AR inhibitory agents to improve the quality and quantity of life of mCRPC patients. Importantly, the C-terminal ligand binding domain (LBD) of the AR represents the direct or indirect molecular target of all hormonally acting agents in clinical use. Other major domains of the AR, including the centrally located DNA binding domain (DBD) and N-terminal transactivation domain (TAD), have yet to be directly targeted and exploited for therapeutic benefit. Given that the AR principally functions as a transcription factor and its genotropic effects are required for the development of castration resistance, we hypothesized that approaches to inhibit AR transcriptional activity by interfering with the TAD will suppress the growth of AR-dependent CRPC cells. In pursuit of this hypothesis, the PIs have collaborated for the last several years to identify a series (the ?JN? series) of potent AR inhibitors with the following characteristics: 1) AR TAD as the molecular target, 2) direct, selective, high affinity and covalent binding to the AR, 3) drug-induced rapid degradation of the full-length AR (ARFL) and constitutively active AR splice variants that lack a functional LBD (ARSVs), 4) selective cytoreductive effects on AR expressing prostate cancer cell lines, including AR?LBD expressing cell lines, 5) growth inhibition of CRPC xenografts, and 6) inhibition of AR-driven gene expression. In the advancement of the pre-clinical and clinical development of JN series compounds, we propose to elucidate the detailed mechanism of action of the JN series compounds and identify a lead compound through further structure activity relationship analysis that will be pre-clinically validated and tested in IND-enabling studies. In year 5 of the award, we will initiate a first-in-human phase 1 study of our lead compound.
The investigators propose to identify a small molecule (i.e. drug) that inhibits the androgen receptor (AR), a driver of prostate cancer growth. Drugs that function by targeting a N-terminus of the AR and induce its degradation have been identified in a high throughput drug screen and validated for biochemical and growth inhibitory activity in mammalian prostate cancer systems in vitro and in vivo. We will continue to elucidate the precise mechanism of action of these drugs and develop more related drugs that improve on the activity of the existing ones, and ultimately, the most promising compound will be tested in an early phase clinical trial of patients with advanced prostate cancer.
Showing the most recent 10 out of 339 publications
