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Expert Opin Drug Discov. 2009 May;4(5):525-44. doi: 10.1517/17460440902852686.

Smoothened antagonists: a promising new class of antitumor agents.

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Istituto di Ricerche di Biologia Molecolare P. Angeletti, Department of Oncology, IRBM- Merck Research Laboratories Rome, Via Pontina Km 30,600, 00040 Pomezia, Italy +39 06 91093232 ; +39 06 91093549 ; Christian_Steinkuhler@Merck.Com.



Hedgehog signaling is essential for the development of most metazoans. In recent years, evidence has accumulated showing that many human tumors aberrantly re-activate this developmental signaling pathway and that interfering with it may provide a new strategy for the development of novel anti-cancer therapeutics. Smoothened is a G-protein coupled receptor-like protein that is essentially involved in hedgehog signal transduction and small molecule antagonists of Smoothened have started to show antitumor activity in preclinical models and in clinical trials.


We critically review the role of hedgehog signaling in normal development and in human malignancies, the available drug discovery tools and the classes of small molecule inhibitors that are in development. We further aim to address the potential impact that pathway antagonists may have on the treatment options of cancer patients.


Literature, patents and clinical trial results from the past 5 years were analyzed.


1) A large body of evidence suggests a frequent reactivation of hedgehog signaling in human cancer. 2) Smoothened is an attractive, highly druggable target with extensive preclinical and initial clinical validation in basal cell carcinoma. Several promising novel classes of Smoothened antagonists have been discovered and are being developed as anticancer agents. 3) Our knowledge of the biology of hedgehog signaling in cancer is still very incomplete and significant efforts will be required to understand how to use the emerging novel agents in the clinic.


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