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• W2081170157 abstract "Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28." @default.
• W2081170157 created "2016-06-24" @default.
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• W2081170157 date "2009-06-12" @default.
• W2081170157 modified "2023-10-16" @default.
• W2081170157 title "Discovery of a Potent and Orally Active Hedgehog Pathway Antagonist (IPI-926)" @default.
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• W2081170157 doi "https://doi.org/10.1021/jm900305z" @default.
• W2081170157 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/19522463" @default.
• W2081170157 hasPublicationYear "2009" @default.
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