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

Abstract

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.