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Discovery of novel Src homology region 2 domain-containing phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma.
- Source :
-
Hepatology (Baltimore, Md.) [Hepatology] 2014 Jan; Vol. 59 (1), pp. 190-201. Date of Electronic Publication: 2013 Dec 09. - Publication Year :
- 2014
-
Abstract
- Unlabelled: 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.<br />Conclusion: 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 in vitro and in vivo. Further clinical investigation is warranted.<br /> (© 2013 by the American Association for the Study of Liver Diseases.)
- Subjects :
- Animals
Antineoplastic Agents therapeutic use
Apoptosis drug effects
Catalytic Domain
Cell Line, Tumor
Drug Resistance, Neoplasm drug effects
Humans
Mice
Models, Molecular
Niacinamide pharmacology
Niacinamide therapeutic use
Phenylurea Compounds therapeutic use
Protein Tyrosine Phosphatase, Non-Receptor Type 6 chemistry
Random Allocation
STAT3 Transcription Factor antagonists & inhibitors
Sorafenib
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Carcinoma, Hepatocellular drug therapy
Liver Neoplasms drug therapy
Niacinamide analogs & derivatives
Phenylurea Compounds pharmacology
Protein Tyrosine Phosphatase, Non-Receptor Type 6 drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1527-3350
- Volume :
- 59
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Hepatology (Baltimore, Md.)
- Publication Type :
- Academic Journal
- Accession number :
- 23908138
- Full Text :
- https://doi.org/10.1002/hep.26640