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

  • J Med Chem. 2009 Jul 23;52(14):4400-18. doi: 10.1021/jm900305z.
Martin R Tremblay  1 ,  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
Affiliations
  • 1. Infinity Pharmaceuticals, Inc, Cambridge, Massachusetts 02139, USA. [email protected]
PMID: 19522463 DOI: 10.1021/jm900305z
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.