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Discovery of NVP-LEQ506, a second generation inhibitor of Smoothened

He, Feng, Dai, Miao, Zhang, Rui, Sun, Yingchuan, Miller-Moslin, Karen, McEwan, Michael, Lagu, Bharat, Wang, Kate, Kelleher Iii, Joseph, Dorsch, Marion, Buonamici, Silvia, Maniara, Wieslawa, Peukert, Stefan, Bourret, Aaron, Ramamurthy, Arun, Williams, Juliet, Green, John, Amaral, Adam, Vattay, Anthony, Wang, Anlai, Guo, Ribo, Yuan, Jing and Yusuff, Naeem (2013) Discovery of NVP-LEQ506, a second generation inhibitor of Smoothened. ChemMedChem, 8 (8). pp. 1261-1265. ISSN 1860-7179


Inhibition of the Hedgehog (Hh) pathway targeting the Smoothened receptor has proven therapeutic benefit for the treatment of Hh-dependent cancers. Lead optimization provided a novel type of Smoothened inhibitor based on a pyridazine core resulting in the clinical compound NVP-LEQ506. This new agent combines high intrinsic potency and good pharmacokinetic properties resulting in excellent efficacy in preclinical rodent tumor models of medulloblastoma. Activity against a Smo mutant conferring resistance observed in a clinical trial with a competitor compound suggests additional therapeutic potential.

Item Type: Article
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Additional Information: Manuscript is accompanied by a cover page of the issue
Keywords: Hedgehog signalling, Smoothened, antitumor agent
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15


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