Design, Synthesis,\nand Biological Evaluation of Icaritin\nDerivatives as Novel Putative DEPTOR Inhibitors for Multiple Myeloma\nTreatment

Icaritin is an active ingredient\nin Epimedium,\nwhich has a variety of pharmacological activities. However, the low\nactivity of Icaritin and the unclear target greatly limit its application.\nTherefore, based on the structure of Icaritin, we adopted the strategy\nof replacing toxic groups and introducing active groups to design\nand synthesize a series of new analogues. The top compound C3 exhibited better antimultiple myeloma activity with an IC50 of 1.09 μM for RPMI 8226 cells, induced RPMI 8226 apoptosis,\nand blocked the cell cycle in the S phase. Importantly, transcriptome\nanalysis, cellular thermal shift assay, and microscale thermophoresis\nassay confirmed that DEPTOR was the target of C3. Moreover,\nwe explored its binding mode with C3. Especially, C3 displayed satisfactory inhibition of tumor growth in RPMI\n8226 xenografts without obvious side effects. In summary, C3 was discovered as a novel putative inhibitor of DEPTOR for the treatment\nof multiple myeloma.