Eradication of Therapy-Resistant Cancer Stem Cells by Novel Telmisartan Derivatives

The present structure–activity
relationship study investigates
the development of novel chemosensitizers targeting therapy-resistant
cancer stem cells (CSCs). We used 4′-((2-propyl-1H-benzo[d]imidazole-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic
acid, derived from the angiotensin II type 1 receptor blocker telmisartan,
as a lead structure, demonstrating that the biphenyl moiety is essential
for chemosensitizing activity. Introducing a methyl carboxylate or
carboxamide instead of the COOH-group significantly enhanced this
effect, leading to the development of highly potent compounds. These
novel, noncytotoxic chemosensitizers effectively target CSCs and overcome
drug resistance by interfering with CSC persistence mechanismshyperactivated
STAT5 signaling and increased drug transporter activitywith
demonstrated efficacy in leukemia, ovarian, and prostate cancers.
The carboxamide of telmisartan (telmi-amide, 7c) significantly
reduced tumor growth in an imatinib-resistant leukemia xenograft model,
both as monotherapy and combined with imatinib, showing promising
oral bioavailability and tolerability. In summary, telmisartan derivatives
act as effective chemosensitizers and offer an innovative strategy
for targeting CSCs in various malignant diseases.