Development of HSP90 inhibitors-SN38 conjugates for cancer treatment

Presently, chemotherapy remains to be one of the most important therapeutic approaches for malignant tumors. Ligands based drug conjugates are showing considerable promise as potential therapeutic agents delivery sys-tems for cancer. Here, a series of HSP90 inhibitors-SN38 conjugates were developed through cleavable linkers for tumor-specific delivery of SN38 and reducing its side effects. In vitro assays showed that these conjugates exhibited acceptable stability in PBS and plasma, appreciable HSP90 binding affinity, and potent cytotoxic abilities. Cellular uptake behaviors also indicated that these conjugates could selectively target cancer cells in a time-dependent manner via HSP90. Among them, compound 10b with a glycine linkage exhibits appreciable in vitro and in vivo pharmacokinetic profiles, and excellent in vivo antitumor activity in Capan-1 xenograft models, demonstrating the selective targeting and accumulation of the active payload at tumor sites. Above all, these results suggest that compound 10b has the potential as a potent anticancer drug, meriting further evaluation in the future.