Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926).

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.

• Authors: Martin R Tremblay, André Lescarbeau, Michael J Grogan, Eddy Tan, Grace Lin, Brian C Austad, Lin-Chen Yu, Mark L Behnke, Somarajan J Nair, Margit Hagel, Kerry White, James Conley, Joseph D Manna, Teresa M Alvarez-Diez, Jennifer Hoyt, Caroline N Woodward, Jens R Sydor, Melissa Pink, John MacDougall, Matthew J Campbell, Jill Cushing, Jeanne Ferguson, Michael S Curtis, Karen McGovern, Margaret A Read, Vito J Palombella, Julian Adams, Alfredo C Castro
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 14 Pg. 4400-18 (Jul 23 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19522463 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Hedgehog Proteins
• IPI-926
• Veratrum Alkaloids
• cyclopamine

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Cell Line
• Drug Discovery
• Hedgehog Proteins (antagonists & inhibitors, metabolism)
• Humans
• Liver (cytology)
• Medulloblastoma (drug therapy, pathology)
• Microsomes (drug effects, metabolism)
• Signal Transduction (drug effects)
• Stereoisomerism
• Veratrum Alkaloids (administration & dosage, chemistry, pharmacokinetics, pharmacology)