AES-135

AES-135 is a novel small molecule inhibitor belonging to the class of hydroxamic acid-based histone deacetylase (HDAC) inhibitors. It is a chemically unique compound developed through structure-activity relationship studies to repurpose STAT3-targeting scaffolds for HDAC inhibition. AES-135 biochemically inhibits HDACs 3, 6, 8, and 11, with half-maximal inhibitory concentrations (IC50) ranging from 190 to 1100 nM, showing highest potency for HDAC6. In preclinical models, AES-135 demonstrates selective in vitro cytotoxicity for tumor cells over cancer-associated fibroblasts, minimal toxicity to non-cancerous cells, metabolic stability, and sufficient in vivo exposure. Notably, AES-135 prolongs survival in orthotopic mouse models of pancreatic ductal adenocarcinoma (PDAC), with low micromolar activity in patient-derived pancreatic cancer cell lines and efficacy in aggressive PDAC models resistant to standard therapies. Mechanistically, it combines the HDAC inhibitory action of an N-hydroxamic acid motif with a novel chemotype, offering a promising lead candidate for further preclinical development against pancreatic cancer and potentially other malignancies[1][5][7][3].