Journal
DRUG DISCOVERY TODAY
Volume 23, Issue 3, Pages 704-710Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.drudis.2018.01.012
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Funding
- National Natural Science Foundation of China [21572037]
- China Postdoctoral Science Foundation [20130071110071]
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Smoothened (Smo), the main transducer of the Hedgehog (Hh) signaling pathway, is a promising target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been associated with mutation-related drug resistance. In this review, we outline the resistance mechanisms of Smo inhibitors and point the way for future endeavors. We focus in particular on the development of second-generation Smo inhibitors based on co-crystal structures, inhibition of downstream components, and the regulation of other interacting pathways or mediators that could compensate for the inhibitory activity of upstream inhibitors.
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