Aminocholestane and Aminoandrostane Inhibitors of the SH2 Domain-Containing Inositol 5’-Phosphatase (SHIP)

IF 3.4 4区医学 Q2 CHEMISTRY, MEDICINAL ChemMedChem Pub Date : 2025-01-22 DOI:10.1002/cmdc.202400597

Angela M. Pacherille, Dennis R. Viernes, Chiara Pedicone, Sandra Fernandes, Otto M. Dungan, Shawn Dormann, Daniel R. Wallach, Raki Sudan, Robbie Brooks, Christopher M. Russo, Kyle T. Howard, Michael S. Cosgrove, William G. Kerr, John D. Chisholm

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Abstract

The SH2-containing inositol phosphatase (SHIP) has become an actively researched therapeutic target for a number of disorders, including Alzheimer's Disease, Graft-vs-Host disease, obesity and cancer. Analogs of the aminosteroid SHIP inhibitor 3α-aminocholestane (3AC) have been synthesized and tested. Analogs with improved water solubility have been identified. Deletion of the C17 alkyl group from the cholestane skeleton improves water solubility, however these compounds inhibit both SHIP1 and SHIP2. Enzyme kinetics imply that these molecules are competitive inhibitors of SHIP, binding at a site near where the substrate binds to the phosphatase. A model of the binding of the inhibitors within the active site of SHIP1 is proposed to explain the structure activity studies. Overall this work provides more water soluble aminosteroid pan-SHIP1/2 inhibitors that can be used for future studies of SHIP activity.

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含SH2结构域肌醇5′-磷酸酶（SHIP）的氨基胆甾和氨基雄烷抑制剂。

含有sh2的肌醇磷酸酶（SHIP）已成为许多疾病的积极研究治疗靶点，包括阿尔茨海默病、移植物抗宿主病、肥胖和癌症。氨基类固醇SHIP抑制剂3a-氨基胆甾（3AC）的类似物已经合成并进行了测试。已鉴定出具有改善水溶性的类似物。从胆甾烷骨架中删除C17烷基可以改善水溶性，但这些化合物同时抑制SHIP1和SHIP2。酶动力学表明这些分子是SHIP的竞争性抑制剂，结合在底物与磷酸酶结合的位置附近。提出了SHIP1活性位点内抑制剂结合的模型来解释结构活性研究。总的来说，这项工作提供了更多的水溶性氨基类固醇泛ship1 /2抑制剂，可用于未来的SHIP活性研究。

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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.