The Investigation of Hsp90C-Terminal Inhibitors Containing Amide Bioisosteres.

Autor: Amatya E; Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, Indiana, 46556, USA., Subramanian C; Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, Illinois, 61801, United States., Long R; Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, Indiana, 46556, USA., McNamara K; Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, Illinois, 61801, United States., Cohen MS; Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, Illinois, 61801, United States., Blagg BSJ; Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, Indiana, 46556, USA.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2024 Aug 17, pp. e202400418. Date of Electronic Publication: 2024 Aug 17.
DOI: 10.1002/cmdc.202400418
Abstrakt: 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.
(© 2024 Wiley-VCH GmbH.)
Databáze: MEDLINE
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