Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/6139
Title: Acylthiourea, Acylurea and Acylguanidine Derivatives with potent Hedgehog inhibiting Activity
Authors: Solinas, A
Faure, H
Roudaut, H
Traiffort, E
Schoenfelder, A
Mann, A
Manetti, Fabrizio 
Taddei, Maurizio 
Ruat, M.
Issue Date: 2012
Project: None 
Journal: JOURNAL OF MEDICINAL CHEMISTRY
Abstract: 
The Smoothened (Smo) receptor is the major transducer of the Hedgehog (Hh) signaling pathway. On the basisof the structure of the acylthiourea Smo antagonist (MRT-10), a number of different series of analogous compounds wereprepared by ligand-based structural optimization. The acylthioureas, originally identified as actives, were converted into thecorresponding acylureas or acylguanidines. In each series, similar structural trends delivered potent compounds with IC50 valuesin the nanomolar range with respect to the inhibition of the Hh signaling pathway in various cell-based assays and of BODIPYcyclopaminebinding to human Smo. The similarity of their biological activities, in spite of discrete structural differences, mayreveal the existence of hydrogen-bonding interactions between the ligands and the receptor pocket. Biological potency ofcompounds 61, 72, and 86 (MRT-83) were comparable to those of the clinical candidate GDC-0449. These findings suggest thatthese original molecules will help delineate Smo and Hh functions and can be developed as potential anticancer agents.
Description: 
39858
URI: http://hdl.handle.net/20.500.12779/6139
ISSN: 0022-2623
DOI: 10.1021/jm2013369
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