The novel selective HDAC1 inhibitor ZJH-1 exhibits potent antitumor activity in castration-resistant prostate cancer, potentially involving HSP90AA1.

Histone deacetylase (HDAC) inhibitors are being explored as a therapeutic approach for prostate cancer (PCa), particularly castration-resistant variants with limited treatment options. In this study, we designed and synthesized ZJH-1, a novel hydroxamate-based HDAC1-selective inhibitor, and systematically evaluated its anti-tumor efficacy and molecular mechanisms. Biochemical and affinity analyses showed ZJH-1 possesses the highest HDAC1 selectivity among isoforms, associated with H3 hyperacetylation at Lys9/27 in PCa cells. ZJH-1 demonstrated cytotoxic effects (IC50 = 65 nM in PC3 cells and 345 nM in patient-derived xenograft organoids (PDXOs)) via dual mechanisms: 1) cell cycle modulation, inducing G1 arrest through Cyclin D1 downregulation; and 2) intrinsic apoptosis induction, evidenced by caspase-3 cleavage and an elevated Bax/Bcl-2 ratio. ZJH-1 also showed potential to affect metastasis-related processes, as suggested by reduced activity of MMP-2/MMP-9 and reversed markers of epithelial-mesenchymal transition (EMT). Network pharmacology analysis predicted HSP90AA1 as a potential docking target of ZJH-1. Furthermore, protein expression analysis demonstrated that ZJH-1 upregulates disabled homolog 2 interacting protein (DAB2IP) and downregulates heat shock protein 90AA1 (HSP90AA1). In vivo, ZJH-1 (20 mg/kg, i.p.) significantly attenuated tumor growth in PC3 xenograft models (75 % volume reduction vs. controls) with no obvious weight loss or overt toxic side effects observed. These findings suggest that ZJH-1, a selective HDAC1 inhibitor, merits further investigation as a potential treatment for PCa.