Compound C9(Hebei University)

Protein palmitoylation is a crucial posttranslational lipid modification and exerts an influence on various cancer‐related factors and is directly implicated in the pathogenesis of malignant tumors. The study used the original ligand phosphate‐adenosine‐5′‐diphosphateas (PAP) of palmitoyltransferase (DHHC) as the lead compound, designed and synthesized two series of pyrazolo[3,4‐ d ]pyrimidine derivatives as DHHC inhibitors. Among them, compound C9 displayed superior DHHC inhibitory activity compared with PAP, and the best antiproliferative activity against MC38 cells with low toxicity. In vitro, it manifested excellent abilities in inhibiting cancer cell migration and invasion, promoting cancer cell apoptosis, and arresting the cells in the G 0 /G 1 phase. Molecular docking studies showed that C9 could occupy the PAP binding site and enhance interactions with surrounding amino acid residues. Molecular dynamics simulations showed that C9 could stably bind to DHHC. These findings highlight the potential of C9 as a novel and potent palmitoyltransferase inhibitor that deserves further investigation.