HSP90/LSD1 dual inhibitors against prostate cancer as well as patient-derived colorectal organoids

The rational installation of pharmacophores targeting HSP90 and LSD1 axes has achieved significant anti-cancer capacity in prostate and colorectal cancer. Among the series of hybrids, inhibitor 6 exhibited remarkable anti-proliferative activity against prostate cancer cell lines PC-3 and DU145, with GI50 values of 0.24 and 0.30 μM, respectively. It demonstrated notable efficacy in combinatorial attack and cell death initiation towards apoptosis. The cell death process was mediated by PARP induction and γH2AX signaling, and was also characterized as caspase-dependent and Bcl-xL/Bax-independent. Notably, no difference in eye size or morphology was observed in the zebrafish treated with compound 6 compared to the reference group (AUY922). The profound treatment response in docetaxel-resistant PC-3 cells highlighted the dual inhibitory ability in improving docetaxel sensitivity. Additionally, at a minimum concentration of 1.25 μM, compound 6 effectively inhibited the growth of patient-derived colorectal cancer (CRC) organoids for up to 10 days in vitro. Together, the designed HSP90/LSD1 inhibitors present a novel route and significant clinical value for anti-cancer drug therapy. [Display omitted] •Compound 6 exhibited potent dual LSD1/HSP90 inhibition at both enzymatic and cellular levels.•Compound 6 induced apoptosis in prostate cancer cells and sustained cytotoxicity against docetaxel resistance.•Compound 6 was regarded innocuous to noncancerous fibroblast cells and zebrafish compared to reference compounds.•Compound 6 displayed anti-tumor activity in patient-derived organoids of colorectal cancer.