The Investigation of Hsp90C-Terminal Inhibitors Containing Amide Bioisosteres.

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2024-08-17 DOI:10.1002/cmdc.202400418

Eva Amatya, Chitra Subramanian, Reagan Long, Kelli McNamara, Mark S Cohen, Brian S J Blagg

引用次数: 0

Abstract

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, SKMel19 and A375 cells, respectively.

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研究含有酰胺生物异构体的 Hsp90 C 端抑制剂。

热休克蛋白 90（Hsp90）负责约 400 种客户蛋白底物的正常折叠和成熟，其中许多与癌症的十大特征直接相关。Hsp90 是包括黑色素瘤在内的癌症治疗的一个重要靶点，因为抑制 Hsp90 可以同时破坏多种致癌途径。在这项研究中，我们报告了一系列 Hsp90 C 端抑制剂的合成及其对突变型 BRAF 和野生型 BRAF 黑色素瘤细胞的抗增殖活性。此外，我们还通过引入酰胺生物异构体，探索了新型 Hsp90 C 端抑制剂 6（B1）的酰胺分子的结构-活性关系（SAR）。化合物 6 对 SKMel173、SKMel103、SKMel19 和 A375 细胞的 IC50 分别为 1.01 μM、0.782 μM、0.607 μM 和 1.413 μM。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.