The Investigation of Hsp90 C‐terminal inhibitors containing Amide bioisosteres

Heat Shock Protein 90 (Hsp90) is responsible for the proper folding and maturation of ~400 client protein substrates, many of which are directly associated with the ten hallmarks of cancer. Hsp90 is a great target for cancer therapy including melanoma, since Hsp90 inhibition can disrupt multiple oncogenic pathways simultaneously. In this study, we report the synthesis and anti‐proliferative activity manifested by a series of Hsp90 C‐terminal inhibitors against mutant BRAF and wild‐type BRAF melanoma cells. Furthermore, we explored structure‐activity relationships (SAR) for the amide moiety of 6 ( B1 ), a novel Hsp90C‐terminal inhibitor via introduction of amide bioisosteres. Compound 6 displayed an IC 50 of 1.01 μM, 0.782 μM, 0.607 μM and 1.413 μM against SKMel173, SKMel103, SKMel19 and A375 cells, respectively.