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Identification of a series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as potent smoothened antagonist hedgehog pathway inhibitors
Authors:Ontoria Jesus M  Bufi Laura Llauger  Torrisi Caterina  Bresciani Alberto  Giomini Claudia  Rowley Michael  Serafini Sergio  Bin Hu  Hao Wu  Steinkühler Christian  Jones Philip
Institution:IRBM, Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia, 00040 Rome, Italy.
Abstract:The Hedgehog (Hh-) signalling pathway is a key developmental pathway and there is a growing body of evidence showing that this pathway is aberrantly reactivated in a number of human tumors. Novel agents capable of inhibiting this pathway are sought, and an entirely novel series of smoothened (Smo) antagonists capable of inhibiting the pathway have been identified through uHTS screening. Extensive exploration of the scaffold identified the key functionalities necessary for potency, enabling potent nanomolar Smo antagonists like 91 and 94 to be developed. Optimization resulted in the most advanced compounds displaying low serum shift, clean off-targets profile, and moderate clearance in both rats and dogs. These compounds are valuable tools with which to probe the biology of the Hh-pathway.
Keywords:Hedgehog pathway  Smoothened antagonist  Hedgehog inhibitor
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