SC-60, a Dimer-Based Sorafenib Derivative, Shows a Better Anti–Hepatocellular Carcinoma Effect than Sorafenib in a Preclinical Hepatocellular Carcinoma Model

Tai, Wei-Tien; Shiau, Chung Wai; Li, Yong Shi; Chen, Yao Li; Chu, Pei Yi; Huang, Jui Wen; Hsu, Cheng Yi; Hsu, Yi Chieh; Chen, Pei‐Jer; Chen, Kuen Feng

doi:10.1158/1535-7163.mct-13-0595

Cited by 7 publications

(5 citation statements)

References 30 publications

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“…Sorafenib and its derivatives can form a salt bridge with the D61 residue of SHP-1 in the N-SH2 domain, which releases the auto-inhibition of SHP-1 and activates SHP-1 [ 153 ]. Accumulating data showed that sorafenib and its derivatives can effectively suppress tumor of HCC through SHP1/STAT3 axis [ 21 , 75 , 156 , 157 , 158 , 159 , 160 ]. Some sorafenib derivatives displayed more potent anti-HCC activity than sorafenib, even for sorafenib-resistant HCC cells [ 157 , 158 ].…”

Section: Targeting the Ptps For Therapy In Hepatocellular Carcinommentioning

confidence: 99%

The Roles of Protein Tyrosine Phosphatases in Hepatocellular Carcinoma

Huang

Zhang

et al. 2018

Cancers

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The protein tyrosine phosphatase (PTP) family is involved in multiple cellular functions and plays an important role in various pathological and physiological processes. In many chronic diseases, for example cancer, PTP is a potential therapeutic target for cancer treatment. In the last two decades, dozens of PTP inhibitors which specifically target individual PTP molecules were developed as therapeutic agents. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and is the second most lethal cancer worldwide due to a lack of effective therapies. Recent studies have unveiled both oncogenic and tumor suppressive functions of PTP in HCC. Here, we review the current knowledge on the involvement of PTP in HCC and further discuss the possibility of targeting PTP in HCC.

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Section: Targeting the Ptps For Therapy In Hepatocellular Carcinommentioning

confidence: 99%

The Roles of Protein Tyrosine Phosphatases in Hepatocellular Carcinoma

Huang

Zhang

et al. 2018

Cancers

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“…Additionally, SC-43 was confirmed to act as an SHP-1 agonist in cholangiocarcinoma [ 93 ], CRC [ 94 ], and breast cancer [ 95 ]. SC-60, another sorafenib derivative, also had an anticancer effect by increasing SHP-1 activity in HCC and triple-negative breast cancer (TNBC) [ 93 , 96 , 97 ]. Regorafenib is a multiple protein kinases inhibitor that is very similar to sorafenib, and it enhances SHP-1 activity in HCC and CRC to promote apoptosis by inhibiting STAT3 signaling [ 98 , 99 ].…”

Section: The Function Of Shp-1 and Tumorsmentioning

confidence: 99%

Consideration of SHP-1 as a Molecular Target for Tumor Therapy

Lim,

Lee,

Kim

et al. 2023

IJMS

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Abnormal activation of receptor tyrosine kinases (RTKs) contributes to tumorigenesis, while protein tyrosine phosphatases (PTPs) contribute to tumor control. One of the most representative PTPs is Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1), which is associated with either an increased or decreased survival rate depending on the cancer type. Hypermethylation in the promoter region of PTPN6, the gene for the SHP-1 protein, is a representative epigenetic regulation mechanism that suppresses the expression of SHP-1 in tumor cells. SHP-1 comprises two SH2 domains (N-SH2 and C-SH2) and a catalytic PTP domain. Intramolecular interactions between the N-SH2 and PTP domains inhibit SHP-1 activity. Opening of the PTP domain by a conformational change in SHP-1 increases enzymatic activity and contributes to a tumor control phenotype by inhibiting the activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) pathway. Although various compounds that increase SHP-1 activation or expression have been proposed as tumor therapeutics, except sorafenib and its derivatives, few candidates have demonstrated clinical significance. In some cancers, SHP-1 expression and activation contribute to a tumorigenic phenotype by inducing a tumor-friendly microenvironment. Therefore, developing anticancer drugs targeting SHP-1 must consider the effect of SHP-1 on both cell biological mechanisms of SHP-1 in tumor cells and the tumor microenvironment according to the target cancer type. Furthermore, the use of combination therapies should be considered.

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“…We therefore hypothesized that the interaction of sorafenib (or its derivatives SC-43 and SC-60) and the N-SH2 domain might lead to a release of the D61 catalytic site and activation of SHP-1 activity. Currently, the hypothesized mechanism was supported by using ectopic expressing dN1 (deleted N-SH2) and D61A mutant SHP-1 in cholangiocarcinoma [71], HCC [72], CRC [73], and triple-negative breast cancer (TNBC) [69] cells. Compared to wild-type SHP-1-expressing cells, SC-43 [71,73] and SC-60 [69,72] exerted less p-STAT3 downregulation and apoptosis-promoting effects on these mutant SHP-1-expressing cells.…”

Section: Shp-1/stat3 Pathway Is a Target In The Treatment Of Humanmentioning

confidence: 99%

“…Currently, the hypothesized mechanism was supported by using ectopic expressing dN1 (deleted N-SH2) and D61A mutant SHP-1 in cholangiocarcinoma [71], HCC [72], CRC [73], and triple-negative breast cancer (TNBC) [69] cells. Compared to wild-type SHP-1-expressing cells, SC-43 [71,73] and SC-60 [69,72] exerted less p-STAT3 downregulation and apoptosis-promoting effects on these mutant SHP-1-expressing cells. Compared with sorafenib, SC-1 and SC-43 induced more potent apoptosis in association with downregulation of p-STAT3 and its downstream molecules (cyclin D1 and survivin) in breast cancer cell lines [68].…”

Section: Shp-1/stat3 Pathway Is a Target In The Treatment Of Humanmentioning

confidence: 99%

“…Compared with sorafenib, SC-1 and SC-43 induced more potent apoptosis in association with downregulation of p-STAT3 and its downstream molecules (cyclin D1 and survivin) in breast cancer cell lines [68]. The same mechanism existed in SC-60, a dimer-based sorafenib derivative that successfully exhibits anti-cancer ability in HCC [72] and TNBC [69]. Besides sorafenib, regorafenib, which is an inhibitor of multiple protein kinases, also exerts anti-tumor ability by reactivating SHP-1 and inhibiting STAT3 signaling in metastatic CRC [73,74] and HCC [75].…”

Section: Shp-1/stat3 Pathway Is a Target In The Treatment Of Humanmentioning

confidence: 99%

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Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy

Huang

Su²,

Liu

et al. 2017

IJMS

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The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1), a non-receptor protein tyrosine phosphatase, has been reported as a negative regulator of phosphorylated signal transducer and activator of transcription 3 (STAT3) and linked to tumor development. In this present review, we will discuss the importance and function of SHP-1/p-STAT3 signaling in nonmalignant conditions as well as malignancies, its cross-talk with other pathways, the current clinical development and the potential role of inhibitors of this pathway in anticancer therapy and clinical relevance of SHP-1/p-STAT3 in cancers. Lastly, we will summarize and highlight work involving novel drugs/compounds targeting SHP-1/p-STAT3 signaling and combined strategies that were/are discovered in our and our colleagues’ laboratories.

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SC-60, a Dimer-Based Sorafenib Derivative, Shows a Better Anti–Hepatocellular Carcinoma Effect than Sorafenib in a Preclinical Hepatocellular Carcinoma Model

Cited by 7 publications

References 30 publications

The Roles of Protein Tyrosine Phosphatases in Hepatocellular Carcinoma

The Roles of Protein Tyrosine Phosphatases in Hepatocellular Carcinoma

Consideration of SHP-1 as a Molecular Target for Tumor Therapy

Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy

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