Key determinants of the chemo-sensitizing activity of novel Telmisartan derivatives

Maximilian Gebhart , Christian A. Elvert , Anna M. Schoepf , Alexandra Scheiber , Stefan Schwaiger , Cornelia A. Karg , Ronald Gust , Stefan Salcher
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引用次数: 0

Abstract

Despite the success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML), resistance remains a major challenge due to target mutations and drug efflux. To counter this, chemo-sensitizers - non-cytotoxic agents that restore drug sensitivity - are being explored. A promising approach involves Telmisartan (1)-based cell death modulators, which may help overcome TKI resistance. Modification of the 2-COOH group of Telmisartan to a carboxamide (2-CONH2, Telmiamide (2)) or methyl ester (2-CO2CH3, Telmiester (3)) transformed these derivatives into potent inhibitors of the efflux transporter ABCB1 and the STAT5 protein - two critical mediators of CML persistence during TKI therapy. Both compounds successfully restored Imatinib (Im) sensitivity in TKI-resistant CML cells. The present structure-activity relationship (SAR) analysis demonstrated that substituent modifications at 2-CONH2 and 2-CO2CH3 significantly influenced biological efficacy, stability in cell culture medium, cellular uptake in CML cells, and inhibition of ABCB1 and STAT5. Among the tested compounds, propyl-, butyl-, phenyl-, and 4-phenoxyphenyl-substituted Telmiamides (2a-d) and Telmiesters (3a-d) exhibited strong chemo-sensitizing potential in vitro, with a half-maximal sensitizing concentration (SC50) < 0.5 μM. Additionally, most derivatives showed improved stability in cell culture, enhancing their suitability for future in vivo studies. When considering cellular uptake in CML cells, these compounds displayed ABCB1 inhibition comparable to the efflux transporter inhibitor Elacridar (E). Notably, their dual mode of action, combining potent ABCB1 and STAT5 inhibition with low cytotoxicity, offers a distinct advantage over Elacridar (E). ADME (absorption, distribution, metabolism, and excretion) studies identified significant limitations in the phenyl carboxamide derivative (2c), revealing low permeability and high metabolism due to the bound phenyl ring. These findings indicate that aromatic residues at the 2-CONH-R group may compromise bioavailability, highlighting a key structural constraint to address in the future optimization of Telmisartan derivatives for therapeutic development. Overall, the study highlights Telmisartan-based derivatives as promising candidates for overcoming TKI resistance in CML and warrants further optimization for clinical translation.

Abstract Image

新型替米沙坦衍生物的化学增敏活性的关键决定因素
尽管酪氨酸激酶抑制剂(TKIs)在治疗慢性髓性白血病(CML)方面取得了成功,但由于靶点突变和药物外排,耐药性仍然是一个主要挑战。为了解决这个问题,人们正在探索化学增敏剂——一种恢复药物敏感性的非细胞毒性药物。基于替米沙坦(1)的细胞死亡调节剂是一种有希望的方法,它可能有助于克服TKI耐药性。将替米沙坦的2- cooh基团修饰为羧酰胺(2- conh2, Telmiamide(2))或甲酯(2- co2ch3, Telmiester(3)),将这些衍生物转化为外排转运体ABCB1和STAT5蛋白的有效抑制剂,这两种蛋白是TKI治疗期间CML持续的关键介质。这两种化合物都成功地恢复了tki耐药CML细胞对伊马替尼(Imatinib)的敏感性。本构效关系(SAR)分析表明,2-CONH2和2-CO2CH3的取代基修饰显著影响了生物功效、细胞培养基稳定性、CML细胞摄取以及ABCB1和STAT5的抑制作用。在测试的化合物中,丙基-、丁基-、苯基-和4-phenoxyphenyl-取代的Telmiamides (2a-d)和Telmiesters (3a-d)在体外表现出较强的化学致敏潜力,具有半最大致敏浓度(SC50) <;0.5μM。此外,大多数衍生物在细胞培养中表现出更好的稳定性,增强了它们在未来体内研究中的适用性。当考虑CML细胞的细胞摄取时,这些化合物显示出与外排转运蛋白抑制剂埃拉西达(E)相当的ABCB1抑制作用。值得注意的是,它们的双重作用模式,结合了有效的ABCB1和STAT5抑制和低细胞毒性,比埃拉西达具有明显的优势(E)。ADME(吸收、分布、代谢和排泄)研究发现了苯基羧胺衍生物的显著局限性(2c),揭示了由于结合苯基环而导致的低渗透性和高代谢。这些发现表明,2-CONH-R基团上的芳香残基可能会影响生物利用度,这突出了未来优化替米沙坦衍生物用于治疗开发的关键结构限制。总的来说,该研究强调了替米沙坦衍生物是克服CML中TKI耐药性的有希望的候选者,并且值得进一步优化临床翻译。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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