2-Amino-3-methylcarboxy-5-heptyl-thiophene (TJ191) is a selective anti-cancer small molecule that targets low TβRIII-expressing malignant T-cell leukemia/lymphoma cells
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Ahmed El-Gazzar1, Sam Noppen1, Joice Thomas2, Wim Dehaen2, Jan Balzarini1 and Sandra Liekens1
1Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, 3000 Leuven, Belgium
2Department of Chemistry, KU Leuven, 3000 Leuven, Belgium
Sandra Liekens, email: [email protected]
Keywords: cytostatic/cytotoxic anti-cancer molecule, T-cell leukemia/lymphoma, TβRIII
Received: July 28, 2017 Accepted: October 05, 2017 Published: December 15, 2017
Current chemotherapy regimens often include non-specific cytostatic/cytotoxic drugs, which do not distinguish between normal and tumor cells, therefore causing considerable systemic toxicity. We previously reported the synthesis and anti-proliferative activity of a novel synthetic 2-aminothiophene-3-carboxylic acid ester derivative TJ191 that selectively targets certain cancer cells without affecting the proliferation of other cancer cells or normal fibroblasts or immune cells (over 600-fold selectivity). In a panel of ten human T-cell leukemia/lymphoma cell lines and peripheral blood mononuclear cells (PBMCs), we now found that transforming growth factor β type III receptor (TβRIII) expression correlates inversely with TJ191 sensitivity, but not with sensitivity against classical chemotherapeutic drugs, thus serving as a predictive marker for TJ191 sensitivity. Accordingly, CRISPR/Cas9-mediated knock-out of TβRIII partially restored the susceptibility of TJ191-resistant cells to this novel compound. Our findings highlight TJ191 as a potent and selective anti-cancer molecule with pronounced activity against human malignant T-cells expressing low levels of TβRIII.
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