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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
13
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pubmed:dateCreated |
2009-7-2
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:AmaralAdamA,
pubmed-author:BourretAaronA,
pubmed-author:DaiMiaoM,
pubmed-author:DorschMarionM,
pubmed-author:GERCJJ,
pubmed-author:JainRishi KRK,
pubmed-author:KarkiRajeshR,
pubmed-author:KelleherJoseph FJF3rd,
pubmed-author:LeiHuangshuH,
pubmed-author:LiYanhongY,
pubmed-author:LlamasLuisL,
pubmed-author:ManiaraWieslawaW,
pubmed-author:MatsumotoMelissaM,
pubmed-author:McEwanMichael AMA,
pubmed-author:Miller-MoslinKarenK,
pubmed-author:PerezLawrenceL,
pubmed-author:PeukertStefanS,
pubmed-author:RamamurthyArunA,
pubmed-author:ShengTaoT,
pubmed-author:SunYingchuanY,
pubmed-author:TianGG,
pubmed-author:VattayAnthonyA,
pubmed-author:WalterMichaelM,
pubmed-author:WilliamsJulietJ,
pubmed-author:YuanJingJ,
pubmed-author:YusuffNaeemN,
pubmed-author:ZhangRuiR
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pubmed:issnType |
Electronic
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pubmed:day |
9
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pubmed:volume |
52
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3954-68
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pubmed:meshHeading |
pubmed-meshheading:19469545-Administration, Oral,
pubmed-meshheading:19469545-Animals,
pubmed-meshheading:19469545-Antineoplastic Agents,
pubmed-meshheading:19469545-Hedgehog Proteins,
pubmed-meshheading:19469545-Humans,
pubmed-meshheading:19469545-Medulloblastoma,
pubmed-meshheading:19469545-Mice,
pubmed-meshheading:19469545-Neoplasms, Experimental,
pubmed-meshheading:19469545-Phthalazines,
pubmed-meshheading:19469545-Receptors, G-Protein-Coupled,
pubmed-meshheading:19469545-Signal Transduction,
pubmed-meshheading:19469545-Structure-Activity Relationship
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pubmed:year |
2009
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pubmed:articleTitle |
1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity.
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pubmed:affiliation |
Department of Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 01239, USA. karen.miller@novartis.com
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pubmed:publicationType |
Journal Article
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