Castration-resistant prostate cancer (CRPC) is currently incurable and makes prostate cancer the second most common cause of cancer death among men in the United States. Multiple studies have shown that the androgen receptor (AR) is activated via multiple mechanisms including AR overexpression, mutation, hypersensitization, and/or intratumoral androgen synthesis in patients relapsed after androgen deprivation therapy (ADT). Almost all the patients develop CRPC following ADT. Overexpression and knockdown studies have shown that AR is a key molecular determinant and an excellent therapeutic target for CRPC. AR is a transcription factor and AR can transactivate its target genes only when it is localized in the nucleus. Pitt researchers have identified and investigated a novel series of analogs that effectively inhibit AR nuclear localization via inducing AR degradation in the nucleus. In developing a potent inhibitor of CRPC, researchers discovered that compounds 1 and 2 reduce levels of prostate specific antigen (PSA), a key marker for CRPC.
Description
Innovators at the University of Pittsburgh have identified novel small molecules that bind to the androgen receptor (AR) and block the nuclear localization and function of AR in CRPC cells. The compounds are not cytotoxic and decrease nuclear AR levels in CRPC cells. Xenograft studies using these small molecules showed inhibition of castration-resistant growth of C4-2 and 22Rv1 xenograft tumors in SCID mice. This work demonstrates the potential of these compounds in CRPC tumor therapy. A second class of compounds significantly decreases cell proliferation in AR-positive cell lines while they have no effect on proliferation in AR-negative cell lines.
Applications
· Potential to inhibit endogenous AR signaling in CRPC cells
· Potential to inhibit the growth of CRPC tumors
· Potential to inhibit androgen dependent tumors
Advantages
· No cytotoxicity
· Very effective in inducing AR degradation in the nucleus
· Lead compounds are effective against all tested AR-positive prostate cancer cell lines
Invention Readiness
In vivo and In vitro data.
IP Status
https://patents.google.com/patent/US10004730B2; https://patents.google.com/patent/US10882834B2; https://patents.google.com/patent/US10544110B2; https://patents.google.com/patent/US10980806B2; https://patents.google.com/patent/US9708276B2; https://patents.google.com/patent/US9981974B2
