title: 1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity.
abstract: Abnormal activation of the Hedgehog (Hh) signaling pathway has been linked to several types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising route toward novel anticancer therapeutics. A cell-based screen performed in our laboratories identified a new class of Hh pathway inhibitors, 1-amino-4-benzylphthalazines, that act via antagonism of the Smoothened receptor. A variety of analogues were synthesized and their structure-activity relationships determined. This optimization resulted in the discovery of high affinity Smoothened antagonists, one of which was further profiled in vivo. This compound displayed a good pharmacokinetic profile and also afforded tumor regression in a genetic mouse model of medulloblastoma.
authors.affiliation: Department of Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 01239, USA. karen.miller@novartis.com
authors.forename: Karen
authors.initials: K
authors.lastname: Miller-Moslin
authors.forename: Stefan
authors.initials: S
authors.lastname: Peukert
authors.forename: Rishi K
authors.initials: RK
authors.lastname: Jain
authors.forename: Michael A
authors.initials: MA
authors.lastname: McEwan
authors.forename: Rajesh
authors.initials: R
authors.lastname: Karki
authors.forename: Luis
authors.initials: L
authors.lastname: Llamas
authors.forename: Naeem
authors.initials: N
authors.lastname: Yusuff
authors.forename: Feng
authors.initials: F
authors.lastname: He
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Li
authors.forename: Yingchuan
authors.initials: Y
authors.lastname: Sun
authors.forename: Miao
authors.initials: M
authors.lastname: Dai
authors.forename: Lawrence
authors.initials: L
authors.lastname: Perez
authors.forename: Walter
authors.initials: W
authors.lastname: Michael
authors.forename: Tao
authors.initials: T
authors.lastname: Sheng
authors.forename: Huangshu
authors.initials: H
authors.lastname: Lei
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Juliet
authors.initials: J
authors.lastname: Williams
authors.forename: Aaron
authors.initials: A
authors.lastname: Bourret
authors.forename: Arun
authors.initials: A
authors.lastname: Ramamurthy
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.forename: Ribo
authors.initials: R
authors.lastname: Guo
authors.forename: Melissa
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Anthony
authors.initials: A
authors.lastname: Vattay
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Maniara
authors.forename: Adam
authors.initials: A
authors.lastname: Amaral
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Kelleher
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010793:Phthalazines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D010793:Phthalazines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; C491022:Smo protein, mouse; D000072086:Smoothened Receptor