α‐Ketobenzothiazole Serine Protease Inhibitors of Aberrant HGF/c‐MET and MSP/RON Kinase Pathway Signaling in Cancer

Han, Zhenfu; Harris, Peter K.; Karmakar, Partha; Kim, Tommy; Owusu, Ben Y.; Wildman, Scott A.; Klampfer, Lidija; Janetka, James W.

doi:10.1002/cmdc.201500600

Cited by 34 publications

(53 citation statements)

References 61 publications

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“…Both the MET kinase inhibitor JNJ38877605 and SRI 31215 inhibit signaling between cancer cells and HGF-producing fibroblasts, blocking fibroblast-induced proliferation, EMT and migration of cancer cells. We confirmed that structurally distinct triplex inhibitors of matriptase, hepsin and HGFA block the crosstalk between tumor cells and fibroblasts [ 66 ]. Furthermore, we demonstrated that SRI 31215 overcomes fibroblast-mediated resistance to EGFR inhibitors in colon cancer cells.…”

Section: Discussionsupporting

confidence: 63%

Inhibition of pro-HGF activation by SRI31215, a novel approach to block oncogenic HGF/MET signaling

et al. 2016

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The binding of hepatocyte growth factor (HGF) to its receptor MET activates a signaling cascade that promotes cell survival, proliferation, cell scattering, migration and invasion of malignant cells. HGF is secreted by cancer cells or by tumor-associated fibroblasts as pro-HGF, an inactive precursor. A key step in the regulation of HGF/MET signaling is proteolytic processing of pro-HGF to its active form by one of the three serine proteases, matriptase, hepsin or HGF activator (HGFA).We developed SRI 31215, a small molecule that acts as a triplex inhibitor of matriptase, hepsin and HGFA and mimics the activity of HAI-1/2, endogenous inhibitors of HGF activation. We demonstrated that SRI 31215 inhibits fibroblast-induced MET activation, epithelial-mesenchymal transition and migration of cancer cells. SRI 31215 overcomes primary resistance to cetuximab and gefitinib in HGF-producing colon cancer cells and prevents fibroblast-mediated resistance to EGFR inhibitors. Thus, SRI 31215 blocks signaling between cancer cells and fibroblasts and inhibits the tumor-promoting activity of cancer-associated fibroblasts.Aberrant HGF/MET signaling supports cell survival, proliferation, angiogenesis, invasion and metastatic spread of cancer cells, establishing HGF and MET as valid therapeutic targets. Our data demonstrate that inhibitors of HGF activation, such as SRI 31215, merit investigation as potential therapeutics in tumors that are addicted to HGF/MET signaling. The findings reported here also indicate that inhibitors of HGF activation overcome primary and acquired resistance to anti-EGFR therapy, providing a rationale for concurrent inhibition of EGFR and HGF to prevent therapeutic resistance and to improve the outcome of cancer patients.

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Section: Discussionsupporting

confidence: 63%

Inhibition of pro-HGF activation by SRI31215, a novel approach to block oncogenic HGF/MET signaling

et al. 2016

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“…Moreover, structural analysis of the complexes of KD1 and HGF/SF‐activating proteases may have significant implications for the development of synthetic chemicals that specifically inhibit proteolytic activation of HGF/SF and MSP. To date, several promising small molecular weight compounds that specifically inhibit the HGF/SF‐activating proteases have been reported . Generation of neutralizing antibodies against these proteases may also be a useful approach.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Hepatocyte growth factor activator inhibitors (HAI‐1 and HAI‐2): Emerging key players in epithelial integrity and cancer

Kataoka

Kawaguchi

Fukushima

et al. 2018

Pathology International

129

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The growth, survival, and metabolic activities of multicellular organisms at the cellular level are regulated by intracellular signaling, systemic homeostasis and the pericellular microenvironment. Pericellular proteolysis has a crucial role in processing bioactive molecules in the microenvironment and thereby has profound effects on cellular functions. Hepatocyte growth factor activator inhibitor type 1 (HAI-1) and HAI-2 are type I transmembrane serine protease inhibitors expressed by most epithelial cells. They regulate the pericellular activities of circulating hepatocyte growth factor activator and cellular type II transmembrane serine proteases (TTSPs), proteases required for the activation of hepatocyte growth factor (HGF)/scatter factor (SF). Activated HGF/SF transduces pleiotropic signals through its receptor tyrosine kinase, MET (coded by the proto-oncogene MET), which are necessary for cellular migration, survival, growth and triggering stem cells for accelerated healing. HAI-1 and HAI-2 are also required for normal epithelial functions through regulation of TTSP-mediated activation of other proteases and protease-activated receptor 2, and also through suppressing excess degradation of epithelial junctional proteins. This review summarizes current knowledge regarding the mechanism of pericellular HGF/SF activation and highlights emerging roles of HAIs in epithelial development and integrity, as well as tumorigenesis and progression of transformed epithelial cells.

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“…In urological cancers, several small molecule inhibitors targeting MET have been used in PC and RCC in clinical trials, and cavozantinib is used as a major agent targeting MET and VEGFR in patients with advanced RCC [90,91,108,109]. In addition, the efficacy of several agents for HGF and the activating TTSPs, including anti-HGF antibody, antibodies and small molecule inhibitors of hepsin and matriptase, has been reported [3,40,[110][111][112][113]. Unfortunately, however, no such specific inhibitors have been verified in clinical trials [3,10].…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

Mukai

Yamasaki

Fujisawa

et al. 2020

IJMS

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Unlike in normal epithelium, dysregulated overactivation of various proteases have been reported in cancers. Degradation of pericancerous extracellular matrix leading to cancer cell invasion by matrix metalloproteases is well known evidence. On the other hand, several cell-surface proteases, including type II transmembrane serine proteases (TTSPs), also induce progression through activation of growth factors, protease activating receptors and other proteases. Hepatocyte growth factor (HGF) known as a multifunctional growth factor that upregulates cancer cell motility, invasiveness, proliferative, and anti-apoptotic activities through phosphorylation of MET (a specific receptor of HGF). HGF secreted as inactive zymogen (pro-HGF) from cancer associated stromal fibroblasts, and the proteolytic activation by several TTSPs including matriptase and hepsin is required. The activation is strictly regulated by HGF activator inhibitors (HAIs) in physiological condition. However, downregulation is frequently observed in cancers. Indeed, overactivation of MET by upregulation of matriptase and hepsin accompanied by the downregulation of HAIs in urological cancers (prostate cancer, renal cell carcinoma, and bladder cancer) are also reported, a phenomenon observed in cancer cells with malignant phenotype, and correlated with poor prognosis. In this review, we summarized current reports focusing on TTSPs, HAIs, and MET signaling axis in urological cancers.

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α‐Ketobenzothiazole Serine Protease Inhibitors of Aberrant HGF/c‐MET and MSP/RON Kinase Pathway Signaling in Cancer

Cited by 34 publications

References 61 publications

Inhibition of pro-HGF activation by SRI31215, a novel approach to block oncogenic HGF/MET signaling

Inhibition of pro-HGF activation by SRI31215, a novel approach to block oncogenic HGF/MET signaling

Hepatocyte growth factor activator inhibitors (HAI‐1 and HAI‐2): Emerging key players in epithelial integrity and cancer

Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

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