Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926).
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.
Tremblay
Martin R
MR
Infinity Pharmaceuticals, Inc, Cambridge, Massachusetts 02139, USA. Martin.Tremblay@infi.com
Lescarbeau
André
A
Grogan
Michael J
MJ
Tan
Eddy
E
Lin
Grace
G
Austad
Brian C
BC
Yu
Lin-Chen
LC
Behnke
Mark L
ML
Nair
Somarajan J
SJ
Hagel
Margit
M
White
Kerry
K
Conley
James
J
Manna
Joseph D
JD
Alvarez-Diez
Teresa M
TM
Hoyt
Jennifer
J
Woodward
Caroline N
CN
Sydor
Jens R
JR
Pink
Melissa
M
MacDougall
John
J
Campbell
Matthew J
MJ
Cushing
Jill
J
Ferguson
Jeanne
J
Curtis
Michael S
MS
McGovern
Karen
K
Read
Margaret A
MA
Palombella
Vito J
VJ
Adams
Julian
J
Castro
Alfredo C
AC
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*
D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; C541444:IPI-926; D014704:Veratrum Alkaloids; C000541:cyclopamine