Cover image for Vol. 12 Issue 15

Editorial Board Chairs: Karl-Heinz Altmann, Antonello Mai, Rainer Metternich. Editor: David Peralta

Impact Factor: 3.225

ISI Journal Citation Reports © Ranking: 2016: 17/60 (Chemistry Medicinal); 73/256 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics

July 03, 2013

VIP: Discovery of NVP-LEQ506, a Second-Generation Inhibitor of Smoothened

VIP: Discovery of NVP-LEQ506, a Second-Generation Inhibitor of SmoothenedStefan Peukert,* Feng He, Miao Dai, Rui Zhang, Yingchuan Sun, Karen Miller-Moslin, Michael McEwan, Bharat Lagu, Kate Wang, Naeem Yusuff, Aaron Bourret, Arun Ramamurthy, Wieslawa Maniara, Adam Amaral, Anthony Vattay, Anlai Wang, Ribo Guo, Jing Yuan, John Green, Juliet Williams, Silvia Buonamici, Joseph F. Kelleher III, Marion Dorsch

In recent years, the Smoothened (Smo) receptor has emerged as a validated drug target for the treatment of a range of Hedgehog-signaling-dependent tumors. These include the most common skin cancer basal cell carcinoma (BCC) and the aggressive brain tumor medulloblastoma, which affects primarily children. The currently approved drug treatment aimed at this target is limited to locally advanced or metastatic BCC and is hampered by the emergence of resistance. A research effort by the Novartis Institutes of Biomedical Research in Cambridge, MA (USA) has identified a new class of Smo inhibitors that could overcome some of the current limitations. Through medicinal chemistry efforts and drug scaffold optimizations, Peukert and co-workers discovered NVP-LEQ506. This second-generation Smo antagonist combines high intrinsic potency, drug penetration to the brain, and activity against a resistant Smo mutant previously observed in a patient, all of which underscore its additional therapeutic potential. This drug candidate has shown excellent efficacy in rodent tumor models and is currently in phase I clinical trials.

Received May 15, 2013; published online July 2, 2013, DOI: 10.1002/cmdc.201300217.

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