Novel small‐molecule LG1836 inhibits the in vivo growth of castration‐resistant prostate cancer

Abstract

BackgroundAndrogen deprivation therapy (ADT) is the mainstay of treatment for castration‐resistant prostate cancer (CRPC). Unfortunately, although ADT initially prolongs survival, most patients relapse and develop resistance. Clinical failure of these treatments in CRPC highlights the urgent need to develop novel strategies to more effectively block androgen receptor (AR) signaling and target other oncogenic factors responsible for ADT resistance.MethodsWe developed a small‐molecule compound LG1836 and investigated the in vitro and in vivo activity of LG1836 against CRPC in cellular and animal models.ResultsLG1836 exhibits potent in vitro cytotoxicity in CRPC cells. Mechanistic studies demonstrated that LG1836 inhibits the expression of AR and AR variant 7, partially mediated via proteasome‐dependent protein degradation. LG1836 also suppresses survivin expression and effectively induces apoptosis in CRPC cells. Significantly, as a single agent, LG1836 is therapeutically efficacious in suppressing the in vivo growth of CRPC in the subcutaneous and intraosseous models and extends the survival of tumor‐bearing mice.ConclusionsThese preclinical studies indicate that LG1836 is a promising lead compound for the treatment of CRPC.

A Comprehensive Overview of Small-Molecule Androgen Receptor Degraders: Recent Progress and Future Perspectives

“…The UPS degradation of AR/AR-V7 induced by functional suppression of HSP90 also appears in compound 74 (LG1836). In the context of CWR22Rv1 tumors xenograft, intraperitoneal injection of 5 mg/kg compound 74 can significantly expand the survival of mice . Francesco Morra et al noted that compound 75 (P5091) as a USP7 inhibitor suppresses the proliferation of 22Rv1 cells by degrading AR-FL and AR-V7 .…”

“…In the context of CWR22Rv1 tumors xenograft, intraperitoneal injection of 5 mg/kg compound 74 can significantly expand the survival of mice. 171 Francesco Morra et al noted that compound 75 (P5091) as a USP7 inhibitor suppresses the proliferation of 22Rv1 cells by degrading AR-FL and AR-V7. 172 2−10 μM Enzalutamide and HDAC inhibitor (SAHA) hybrid compound 76 (Zeta55) was found to degrade AR/AR-V7 after suppressing Hsp90 in VCaP cells.…”