Eradication\nof\nTherapy-Resistant Cancer Stem Cells\nby Novel Telmisartan Derivatives

The present structure–activity\nrelationship study investigates\nthe development of novel chemosensitizers targeting therapy-resistant\ncancer stem cells (CSCs). We used 4′-((2-propyl-1<i>H</i>-benzo[<i>d</i>]imidazole-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic\nacid, derived from the angiotensin II type 1 receptor blocker telmisartan,\nas a lead structure, demonstrating that the biphenyl moiety is essential\nfor chemosensitizing activity. Introducing a methyl carboxylate or\ncarboxamide instead of the COOH-group significantly enhanced this\neffect, leading to the development of highly potent compounds. These\nnovel, noncytotoxic chemosensitizers effectively target CSCs and overcome\ndrug resistance by interfering with CSC persistence mechanismshyperactivated\nSTAT5 signaling and increased drug transporter activitywith\ndemonstrated efficacy in leukemia, ovarian, and prostate cancers.\nThe carboxamide of telmisartan (telmi-amide, <b>7c</b>) significantly\nreduced tumor growth in an imatinib-resistant leukemia xenograft model,\nboth as monotherapy and combined with imatinib, showing promising\noral bioavailability and tolerability. In summary, telmisartan derivatives\nact as effective chemosensitizers and offer an innovative strategy\nfor targeting CSCs in various malignant diseases.