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

Maximilian Gebhart; Mostafa Alilou; Ronald Gust; Stefan Salcher

doi:10.1016/j.ejmech.2024.117106

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

Eur J Med Chem. 2024 Nov 26:283:117106. doi: 10.1016/j.ejmech.2024.117106. Online ahead of print.

Authors

Maximilian Gebhart¹, Mostafa Alilou², Ronald Gust³, Stefan Salcher⁴

Affiliations

¹ Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, CCB-Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020 Innsbruck, Austria.
² Department of Pharmacognosy, Institute of Pharmacy, University of Innsbruck, CCB-Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020 Innsbruck, Austria.
³ Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, CCB-Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020 Innsbruck, Austria. Electronic address: rgust@zedat.fu-berlin.de.
⁴ Department of Internal Medicine V, Hematology and Oncology, Tyrolean Cancer Research Institute (TKFI), Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. Electronic address: stefan.salcher@i-med.ac.at.

PMID: 39637828
DOI: 10.1016/j.ejmech.2024.117106

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 the aromatic rings mentoined above 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 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).

Keywords: Cell death modulators; Cellular uptake; Chronic myeloid leukemia; Enzymatic stability; Imatinib resistance; Structure-activity relationship; Telmisartan derivatives.