University of Pittsburgh researchers have identified a novel class of chemical compounds to treat the currently uncurable metastatic castration-resistant prostate cancer (mCRPC).
Description
The pathophysiology of mCRPC tumors is dependent on the androgen receptor, a hormone receptor believed responsible for the development of treatment resistance. Through screening, using a biosensor assay of over 143,000 compounds, various compounds shown to inhibit dihydrotestosterone (DHT) induced androgen receptor-transcriptional intermediary factor 2 (AR-TIF2) positional protein-protein interaction (PPI) formation and/or disrupt pre-existing AR-TIF2 complexes have been identified. These compounds bind to androgen receptors (AR) impacting genes associated with cellular proliferation and disease progression.
Applications
• Treatment of metastatic castration resistant prostate cancer.
Advantages
Prostate cancer (PC) is one of the leading causes of death among men in the western world with 1 in 8 being diagnosed in their lifetimes. Early diagnosis, surgery and treatment can mean those with localized or regional PC will have a 5-year relative survival rate of 99%. However, around 20% of patients develop mCRPC contributing to nearly 30,000 deaths a year in the United States alone.
Current therapeutic approaches for PC target the production or the physiological pathways involving androgens crucial for the growth of prostate cells. In mCRPC patients, these tumors continue to depend on the androgen receptor even in the absence of the androgen, and so are resistant to current treatment options with no current cure for mCRPC. Our approach would disrupt androgen receptor signaling at a molecular level via allosteric modulation and could overcome the development of drug resistance and progression to castration-resistant prostate cancer.
Invention Readiness
The AR-TIF2 PPI biosensor assay performed high-content screening and identified three classes of compounds: hydrobenzo-oxazepin, thiadiazol-5-piperidine-carboxamide and methyl indoles, many with IC50 values <30 M. Further analysis of these compounds identified the key allosteric binding sites and showed these differed from orthosteric ligand binding sites exhibiting greater selectivity and reducing the risk of side effects.
In vitro analysis has identified novel drug candidates for mCRPC therapy. A research strategy to optimize allosteric modulation has been developed for this purpose.
IP Status
https://patents.google.com/patent/WO2024050433A1
