Design, synthesis and bioevaluation of novel hydrazide derivatives as enhancers of immunotherapy and DNA-damage response in antitumor therapy

We have designed and synthesized a series of novel hydrazide-based HDAC3 inhibitors, with the representative compound 8ae demonstrating potent HDAC3 inhibitory activity, having an IC₅₀ value of 311 nM (with a selectivity index SI greater than 32 over other HDACs). Compound 8ae also exhibited significant anti-proliferative activity against five types of cancer cells, with an average inhibitory rate IC₅₀ value of 5.036 μM, and was capable of inhibiting the migration, invasion, and wound healing activities of B16–F10 cells. Further studies revealed that 8ae effectively modulates the expression of Ac-H3 within tumor cells and can degrade PD-L1 in tumor cells through the lysosome pathway mediated by cathepsin B (CTSB). Notably, 8ae also possesses favorable pharmacokinetic properties. In in vivo experiments, the combination of 8ae with the PD-L1 inhibitor NP-19 activated the immune system in melanoma-bearing mice, leading to an enhanced anti-tumor immune response (TGI = 65 %). When combined with olaparib, 8ae significantly enhanced tumor suppressive activity (TGI = 88 %) in a breast cancer mouse model and displayed a favorable safety profile. Collectively, 8ae is a promising HDAC3 inhibitor that warrants further exploration in cancer therapeutic strategies.