Small Molecule Antagonists in Distinct Binding Modes Inhibit Drug-Resistant Mutant of Smoothened

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• 作者：Haiyan Tao¹ ; ⁵ ; Qihui Jin¹ ; Dong-In Koo² ; Xuebin Liao¹ ; Nathan  ; P. Englund¹ ; Yan Wang¹ ; Arun Ramamurthy³ ; Peter  ; G. Schultz² ; Marion Dorsch³ ; ⁶ ; Joseph Kelleher³ ; Xu Wu¹ ; ⁴ ; ^{xwu@cbrc2.mgh.harvard.edu"" rel=""nofollow}
• 刊名：Chemistry & Biology
• 出版年：2011
• 出版时间：22 April 2011
• 年：2011
• 卷：18
• 期：4
• 页码：432-437
• 全文大小：583 K

文摘

Summary

Several small molecule antagonists for Smoothened (Smo) have been developed, and achieved promising preclinical efficacy in cancers that are dependent on Hedgehog (Hh) signaling. However, in a recent clinical study, a drug-resistant D473H SMO mutant was identified that is thought to be responsible for cancer relapse in a patient with medulloblastoma. Here, we report two Smo antagonists that bind to distinct sites, as compared to known antagonists and agonists, and inhibit both wild-type and mutant Smo. These findings provide an insight of the ligand-binding sites of Smo and a basis for the development of potential therapeutics for tumors with drug-resistant Smo mutations.