title: 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.affiliation: Infinity Pharmaceuticals, Inc, Cambridge, Massachusetts 02139, USA. Martin.Tremblay@infi.com
authors.forename: Martin R
authors.initials: MR
authors.lastname: Tremblay
authors.forename: André
authors.initials: A
authors.lastname: Lescarbeau
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Grogan
authors.forename: Eddy
authors.initials: E
authors.lastname: Tan
authors.forename: Grace
authors.initials: G
authors.lastname: Lin
authors.forename: Brian C
authors.initials: BC
authors.lastname: Austad
authors.forename: Lin-Chen
authors.initials: LC
authors.lastname: Yu
authors.forename: Mark L
authors.initials: ML
authors.lastname: Behnke
authors.forename: Somarajan J
authors.initials: SJ
authors.lastname: Nair
authors.forename: Margit
authors.initials: M
authors.lastname: Hagel
authors.forename: Kerry
authors.initials: K
authors.lastname: White
authors.forename: James
authors.initials: J
authors.lastname: Conley
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Manna
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Alvarez-Diez
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hoyt
authors.forename: Caroline N
authors.initials: CN
authors.lastname: Woodward
authors.forename: Jens R
authors.initials: JR
authors.lastname: Sydor
authors.forename: Melissa
authors.initials: M
authors.lastname: Pink
authors.forename: John
authors.initials: J
authors.lastname: MacDougall
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Campbell
authors.forename: Jill
authors.initials: J
authors.lastname: Cushing
authors.forename: Jeanne
authors.initials: J
authors.lastname: Ferguson
authors.forename: Michael S
authors.initials: MS
authors.lastname: Curtis
authors.forename: Karen
authors.initials: K
authors.lastname: McGovern
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Read
authors.forename: Vito J
authors.initials: VJ
authors.lastname: Palombella
authors.forename: Julian
authors.initials: J
authors.lastname: Adams
authors.forename: Alfredo C
authors.initials: AC
authors.lastname: Castro
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D055808:Drug Discovery; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology; D008527:Medulloblastoma / Q000188:drug therapy / Q000473:pathology; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013237:Stereoisomerism; D014704:Veratrum Alkaloids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; C541444:IPI-926; D014704:Veratrum Alkaloids; C000541:cyclopamine