Circumventing Imatinib resistance in CML: Novel Telmisartan-based cell death modulators with improved activity and stability

Abstract

Drug resistance presents a significant challenge in cancer therapy, which has led to intensive research in resistance mechanisms and new therapeutic strategies. In chronic myeloid leukemia (CML), the introduction of Imatinib, the first tyrosine kinase inhibitor (TKI), drastically changed the outcome for patients. However, complete remission still cannot be achieved in a large number of patients in the long term. Therefore, there is a great interest in the design of new drugs to target TKI-resistant cancer cells. A promising approach to enhance the efficacy of Imatinib is the simultaneous application of cell death modulators derived from the Angiotensin II type 1 receptor blocker Telmisartan. The methyl ester (3a) of 4‘-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1’-biphenyl]-2-carboxylic acid (LEAD-acid (4)), which is the structural core of Telmisartan, has already been shown to abolish the resistance of Imatinib in TKI-insensitive CML cells at a concentration of 5 μM. As the ester was expected to be unstable in a biological environment, this study attempted to increase the stability through structural modifications. The methyl group was exchanged for longer (3b (ethyl), 3c (propyl), 3d (butyl) and branched (3e (isopropyl), 3f (tert-butyl)) alkyl chains as well as a phenyl (3g) and 4-phenoxyphenyl (3h) group. Furthermore, the esters were bioisosterically replaced with a respective substituted carboxamide (5a-h). The LEAD-amides (5a-h) showed high stability against esterases, while amidases cleaved only the carboxamides with short alkyl chains to a small extent. Esterases hydrolyzed the LEAD-alkylesters (3a-d) dependent on the chain length with τ_½ = 55-82 min. Esters with branched alkyl chains were stable and introduction of aromatic rings increased the half-life to τ_½ = 280 min and 360 min. In cell culture medium, only 3a-d degraded to 67-78 % after 72 h. However, the uptake studies showed that approximatly 80 % of the esters were accumulated in the cell within the first 1-3 h of incubation. Therefore, it can be concluded that the intact LEAD-esters and LEAD-amides caused the biological effects. The compounds were non-cytotoxic and efficiently sensitized KD225 (K562-resistant) CML cells to Imatinib at a half-maximal sensitizing concentration (SC₅₀) of 1.5-2.9 μM (ester derivatives) and 1.3-11.2 μM (amide derivatives).