Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926)
| Autor: | Matthew Campbell, Eddy Tan, Kerry White, Vito J. Palombella, Julian Adams, James M. Conley, Jennifer Hoyt, Martin R. Tremblay, Margit Hagel, Jens Sydor, Jeanne A. Ferguson, Jill Cushing, Alfredo C. Castro, Somarajan J. Nair, Andre Lescarbeau, Melissa Pink, Joseph D. Manna, Grogan Michael John, Margaret A. Read, Caroline N. Woodward, Grace Lin, Mark L. Behnke, Teresa M. Alvarez-Diez, Michael Curtis, Lin-Chen Yu, John R. MacDougall, Karen McGovern, Brian C. Austad |
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| Rok vydání: | 2009 |
| Předmět: |
Cyclopamine
Veratrum californicum Administration Oral Antineoplastic Agents Pharmacology Cell Line chemistry.chemical_compound In vivo Microsomes Drug Discovery Animals Humans Hedgehog Proteins biology Alkaloid Antagonist Veratrum Alkaloids Biological activity Stereoisomerism biology.organism_classification Hedgehog signaling pathway Veratrum alkaloid chemistry Liver Molecular Medicine Medulloblastoma Signal Transduction |
| Zdroj: | Journal of medicinal chemistry. 52(14) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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