biostudies-literatureAmatya ENational Cancer InstituteNCI NIH HHSe202400418https://www.ebi.ac.uk/biostudies/studies/S-EPMC11649481biostudies-literatureUnknown19(24)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 IC₅₀ of 1.01 μM, 0.782 μM, 0.607 μM and 1.413 μM against SKMel173, SKMel103, SKMel1ChemMedChemThe Investigation of Hsp90C-Terminal Inhibitors Containing Amide Bioisosteres.PMC11649481R01 CA216919CA270147R01 CA270147McNamara KAmatya ECohen MSLong RBlagg BSJSubramanian CfalseThe Investigation of Hsp90C-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 IC₅₀ of 1.01 μM, 0.782 μM, 0.607 μM and 1.413 μM against SKMel173, SKMel103, SKMel12024-01-01T00:00:00Z2024 Dec2026-06-07T05:00:07.01Z2026-06-07T03:06:29.81ZS-EPMC116494813915320310.1002/cmdc.202400418