Abstract 7222: Antiandrogen equipped with HDAC inhibitors activates autophagy-mediated growth inhibition in castrate-resistant prostate cancer

Abstract

Abstract Targeting androgen receptor (AR) by pharmacologic intervention is one of the practical approaches for the treatment of castration-resistant prostate cancer (CRPC). Hence, this study aimed to develop novel molecules that employ multiple mechanisms to inhibit AR expression and curtail the growth of CRPC. The target antiandrogen-equipped histone deacetylase inhibitors were synthesized, adapting the convergent chemistry we used to synthesize the first-generation compounds. The final compounds were characterized using 1H-NMR, 13C-NMR, and high-resolution mass spectrometry. We synthesized and analyzed several compounds, in which KK62 emerged as the lead compound. KK62 significantly inhibits a panel of CRPC cell lines in nanomolar concentrations without causing toxicity to healthy prostate epithelial cells. The molecular analysis suggested that inhibition of AR and AR-splice variants was evident, followed by downregulation of PSA expression in AR-positive CRPC cell lines. Further analysis confirmed that KK62 overcomes dihydrotestosterone (DHT) induced AR signaling and enzalutamide-resistant CRPC cells by downregulating AR and AR-splice variants in CRPC cells. Subsequent analysis confirmed that KK62 induces autophagy signaling by upregulating autophagosome (LC3B) and lysosome (LAMP1) markers expression and facilitating the autophagosome and lysosome fusion, which resulted in the induction of apoptosis in all AR-positive CRPC cell lines. The pro-apoptotic markers, such as BAX and cleaved caspase, were upregulated, whereas the downregulation of pro-survival markers was evident in KK62-treated CRPC cells. Our ongoing castrated and non-castrated xenotransplanted CRPC tumors and Patient-derived xenograft in vivo studies would validate our in vitro findings and confirm that KK62 is a potent compound that may improve therapeutic advances in treating CRPC. Citation Format: Balaji Chandrasekaran, Kiran Kumar Yalla, Ashish Tyagi, Vaibhav Shukla, Neha Tyagi, Bhawna Tyagi, Mohit Vashishta, Adegboyega K Oyelere, Chendil Damodaran. Antiandrogen equipped with HDAC inhibitors activates autophagy-mediated growth inhibition in castrate-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7222.