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

IF 3.6 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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引用次数: 0

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 3a-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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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

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