Development of Novel Triazolo-Thiadiazoles from Heterogeneous “Green” Catalysis as Protein Tyrosine Phosphatase 1B Inhibitors

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Abstract

Condensed-bicyclic triazolo-thiadiazoles were synthesized via an efficient “green” catalyst strategy and identified as effective inhibitors of PTP1B in vitro. The lead compound, 6-(2-benzylphenyl)-3-phenyl-[1,2,4]triazolo[3][1,3,4]thiadiazole (BPTT) was most effective against human hepatoma cells, inhibits cell invasion, and decreases neovasculature in HUVEC and also tumor volume in EAT mouse models. This report describes an experimentally unidentified class of condensed-bicyclic triazolo-thiadiazoles targeting PTP1B and its analogs could be the therapeutic drug-seeds.

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PTP1B as a drug target: recent developments in PTP1B inhibitor discovery.

Sheng Zhang, Zhong-Yin Zhang (2007)

Protein tyrosine phosphatase 1B (PTP1B) is an effective target for the treatment of both type 2 diabetes and obesity; however, targeting PTP1B for drug discovery is challenging because of the highly conserved and positively charged active-site pocket. Tremendous progress has been made in the development of potent and selective PTP1B inhibitors that engage both the active site and no catalytic sites. Several strategies are being pursued to improve the pharmacological properties of PTP1B inhibitors. These new developments suggest that it is feasible to acquire PTP1B-based, small-molecule therapeutics with the requisite potency and selectivity. Future efforts will probably transform the potent and selective PTP1B inhibitors into orally available drugs with desirable physicochemical properties and in vivo efficacies.

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γ-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model

Kodappully Siveen, Kwang Seok Ahn, Tina Ong … (2014)

Angiogenesis is one of the key hallmarks of cancer. In this study, we investigated whether γ-tocotrienol can abrogate angiogenesis-mediated tumor growth in hepatocellular carcinoma (HCC) and if so, through what molecular mechanisms. We observed that γ-tocotrienol inhibited vascular endothelial growth factor (VEGF)-induced migration, invasion, tube formation and viability of HUVECs in vitro. Moreover, γ-tocotrienol reduced the number of capillary sprouts from matrigel embedded rat thoracic aortic ring in a dose-dependent manner. Also, in chick chorioallantoic membrane assay, γ-tocotrienol significantly reduced the blood vessels formation. We further noticed that γ-tocotrienol blocked angiogenesis in an in vivo matrigel plug assay. Furthermore, γ-tocotrienol inhibited VEGF-induced autophosphorylation of VEGFR2 in HUVECs and also suppressed the constitutive activation of AKT/mammalian target of rapamycin (mTOR) signal transduction cascades in HUVECs as well as in HCC cells. Interestingly, γ-tocotrienol was also found to significantly reduce the tumor growth in an orthotopic HCC mouse model and inhibit tumor-induced angiogenesis in HCC patient xenografts through the suppression of various biomarkers of proliferation and angiogenesis. Taken together, our findings strongly suggest that γ-tocotrienol might be a promising anti-angiogenic drug with significant antitumor activity in HCC.

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Identification of protein-tyrosine phosphatase 1B as the major tyrosine phosphatase activity capable of dephosphorylating and activating c-Src in several human breast cancer cell lines.

D Fujita, A Pang, Jeffrey D Bjorge (2000)

c-Src tyrosine kinase activity is elevated in several types of human cancer, and this has been attributed to elevated c-Src expression levels, increased c-Src specific activity, and activating mutations in c-Src. We have found a number of human breast cancer cell lines with elevated c-Src specific activity that also possess elevated phosphatase activity directed against the carboxyl-terminal negative regulatory domain of Src family kinases. To identify this phosphatase, cell extracts from MDA-MB-435S cells were chromatographed and the fractions were assayed for phosphatase activity. Four peaks of phosphatase activity directed against the nonspecific substrate poly(Glu/Tyr) were detected. One peak also dephosphorylated a peptide modeled against the c-Src carboxyl-terminal negative regulatory domain and intact human c-Src. Immunoblotting and immunodepletion experiments identified the phosphatase as protein-tyrosine phosphatase 1B (PTP1B). Examination of several human breast cancer cell lines with increased c-Src activity showed elevated levels of PTP1B protein relative to normal control breast cells. In vitro c-Src reactivation experiments confirmed the ability of PTP1B to dephosphorylate and activate c-Src. In vivo overexpression of PTP1B in 293 cells caused a 2-fold increase of endogenous c-Src kinase activity. Our findings indicate that PTP1B is the primary protein-tyrosine phosphatase capable of dephosphorylating c-Src in several human breast cancer cell lines and suggests a regulatory role for PTP1B in the control of c-Src kinase activity.

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Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 21 September 2015

Publication date Collection: 2015

Volume: 5

Electronic Location Identifier: 14195

Affiliations

[1 ]Laboratory of Chemical Biology, Department of Chemistry, Bangalore University , Palace Road, Bangalore 560001, India

[2 ]Department of Studies in Chemistry, University of Mysore , Manasagangotri, Mysore-570006, India

[3 ]Frontier Research Center for Post-genome Science and Technology, Hokkaido University , Sapporo 0600808, Japan

[4 ]Centre for Molecular Informatics, Department of Chemistry, University of Cambridge , Lensfield Road, CB2 1EW, Cambridge, United Kingdom

[5 ]Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore-117597 , Singapore

[6 ]Department of Botany and Microbiology, College of Science, King Saudi University , Riyadh -11451, Kingdom of Saudi Arabia

[7 ]Department of Studies in Biochemistry, University of Mysore , Manasagangotri, Mysore-570006, India

Author notes

[a ] salundibasappa@ 123456gmail.com

[b ] rangappaks@ 123456gmail.com

[*]

These authors contributed equally to this work.

Article

Publisher Item ID: srep14195

DOI: 10.1038/srep14195

PMC ID: 4585680

PubMed ID: 26388336

SO-VID: 4859e8c2-e1c8-4c74-a21e-0b2abb2e7028

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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

History

Date received : 15 January 2015

Date accepted : 18 August 2015

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Development of Novel Triazolo-Thiadiazoles from Heterogeneous “Green” Catalysis as Protein Tyrosine Phosphatase 1B Inhibitors

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Most cited references 31

PTP1B as a drug target: recent developments in PTP1B inhibitor discovery.

γ-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model

Identification of protein-tyrosine phosphatase 1B as the major tyrosine phosphatase activity capable of dephosphorylating and activating c-Src in several human breast cancer cell lines.

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