Discovery of novel src homology region 2 domain‐containing phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma. Issue 1 (9th December 2013)

• Record Type: Journal Article
• Authors: Tai, Wei‐Tien; Shiau, Chung‐Wai; Chen, Pei‐Jer; Chu, Pei‐Yi; Huang, Hsiang‐Po; Liu, Chun‐Yu; Huang, Jui‐Wen; Chen, Kuen‐Feng
• Is Part Of: Hepatology. Volume 59:Issue 1(2014:Jan.)
• Page Start: 190
• Page End: 201
• Publication Date: 2013-12-09
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.26640
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Sorafenib is the first approved targeted therapeutic reagent for hepatocellular carcinoma (HCC). Here, we report that Src homology region 2 (SH2) domain‐containing phosphatase 1 (SHP‐1) is a major target of sorafenib and generates a series of sorafenib derivatives to search for potent SHP‐1 agonists that may act as better anti‐HCC agents than sorafenib. Sorafenib increases SHP‐1 activity by direct interaction and impairs the association between the N‐SH2 domain and the catalytic protein tyrosine phosphatase domain of SHP‐1. Deletion of the N‐SH2 domain (dN1) or point mutation (D61A) of SHP‐1 abolished the effect of sorafenib on SHP‐1, phosphorylated signal transducer and activator of transcription 3 (p‐STAT3), and apoptosis, suggesting that sorafenib may affect SHP‐1 by triggering a conformational switch relieving its autoinhibition. Molecular docking of SHP‐1/sorafenib complex confirmed our findings in HCC cells. Furthermore, novel sorafenib derivatives SC‐43 and SC‐40 displayed more potent anti‐HCC activity than sorafenib, as measured by enhanced SHP‐1 activity, inhibition of p‐STAT3, and induction of apoptosis. SC‐43 induced substantial apoptosis in sorafenib‐resistant cells and showed better survival benefits than sorafenib in orthotopic HCC tumors. <italic>Conclusion</italic>: In this study, we identified SHP‐1 as a major target of sorafenib. SC‐43 and SC‐40, potent SHP‐1 agonists, showed better anti‐HCC effects than sorafenib <italic>in vitro</italic> and <italic>in vivo</italic>. Further clinical investigation is warranted. (H<sc>epatology</sc> 2014;58:190–201)</p> </abstract>