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Cells 2018, 7(12), 272; https://doi.org/10.3390/cells7120272

Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as Potent Smoothened Inhibitors

Tumor Cell Biology Unit–Core Research Laboratory, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), 50139 Florence, Italy
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Received: 26 October 2018 / Revised: 30 November 2018 / Accepted: 10 December 2018 / Published: 14 December 2018
(This article belongs to the Special Issue Targeting Hedgehog Signaling in Cancer)
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Abstract

Hedgehog-GLI (HH) signaling was originally identified as a critical morphogenetic pathway in embryonic development. Since its discovery, a multitude of studies have reported that HH signaling also plays key roles in a variety of cancer types and in maintaining tumor-initiating cells. Smoothened (SMO) is the main transducer of HH signaling, and in the last few years, it has emerged as a promising therapeutic target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been hampered by severe side effects, low selectivity against cancer stem cells, and the onset of mutation-driven drug resistance. Moreover, SMO antagonists are not effective in cancers where HH activation is due to mutations of pathway components downstream of SMO, or in the case of noncanonical, SMO-independent activation of the GLI transcription factors, the final mediators of HH signaling. Here, we review the current and rapidly expanding field of SMO small-molecule inhibitors in experimental and clinical settings, focusing on a class of acylguanidine derivatives. We also discuss various aspects of SMO, including mechanisms of resistance to SMO antagonists. View Full-Text
Keywords: hedgehog; smoothened; missense mutations; small molecule inhibitors; GLI; cancer; targeted therapy; drug-resistance; acylguanidine derivative hedgehog; smoothened; missense mutations; small molecule inhibitors; GLI; cancer; targeted therapy; drug-resistance; acylguanidine derivative
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Pietrobono, S.; Stecca, B. Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as Potent Smoothened Inhibitors. Cells 2018, 7, 272.

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