帕纳替尼和托法替尼是成熟的激酶抑制剂，并已获得 FDA 批准用于治疗慢性粒细胞白血病和类风湿性关节炎，最近正在各种临床试验中进行研究，以寻找潜在的重新用途。芳烃受体（AhR）是一种影响一系列生理和病理生理活动的转录因子，是许多疾病的治疗靶点。本研究采用分子建模工具和体外测定来鉴定 ponatinib 和 tofacitinib 作为 AhR 配体，阐明它们在 AhR PAS-B 结构域中的结合和分子相互作用。分子对接分析显示，ponatinib 和 tofacitinib 占据初级腔内的中央口袋，类似于 AhR 激动剂 2,3,7,8-四氯二苯并二恶英 (TCDD) 和 (苯并[a]芘) B[a]P。我们的模拟还表明，这些化合物表现出良好的稳定性，稳定了 PAS-B 结构域内的许多热点，包括作为结合袋调节元件的 Dα-Eα 环。结合能计算强调了 ponatinib 优异的预测亲和力，揭示 F295 是维持与两种化合物强相互作用的关键残基。我们的体外数据表明，ponatinib 可作为 AhR 拮抗剂，阻断 TCDD 和 B[a]P 诱导的 AhR 通路下游信号传导。此外，托法替尼和帕纳替尼都会导致强效 AhR 激动剂诱导的 AhR 调节的 CYP1A1 酶活性受损。这项研究揭示了 ponatinib 和 tofacitinib 作为 AhR 的潜在调节剂，为它们在 AhR 相关疾病中的治疗作用提供了宝贵的见解，并增强了我们对激酶抑制剂和 AhR 之间复杂关系的理解。版权所有 © 2024。由 Elsevier Inc. 出版。

Ponatinib and tofacitinib, established kinase inhibitors and FDA-approved for chronic myeloid leukemia and rheumatoid arthritis, are recently undergoing investigation in diverse clinical trials for potential repurposing. The aryl hydrocarbon receptor (AhR), a transcription factor influencing a spectrum of physiological and pathophysiological activities, stands as a therapeutic target for numerous diseases. This study employs molecular modelling tools and in vitro assays to identify ponatinib and tofacitinib as AhR ligands, elucidating their binding and molecular interactions in the AhR PAS-B domain. Molecular docking analyses revealed that ponatinib and tofacitinib occupy the central pocket within the primary cavity, similar to AhR agonists 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and (benzo[a]pyrene) B[a]P. Our simulations also showed that these compounds exhibit good stability, stabilizing many hot spots within the PAS-B domain, including the Dα-Eα loop, which serves as a regulatory element for the binding pocket. Binding energy calculations highlighted ponatinib's superior predicted affinity, revealing F295 as a crucial residue in maintaining strong interaction with the two compounds. Our in vitro data suggest that ponatinib functions as an AhR antagonist, blocking the downstream signaling of AhR pathway induced by TCDD and B[a]P. Additionally, both tofacitinib and ponatinib cause impairment in AhR-regulated CYP1A1 enzyme activity induced by potent AhR agonists. This study unveils ponatinib and tofacitinib as potential modulators of AhR, providing valuable insights into their therapeutic roles in AhR-associated diseases and enhancing our understanding of the intricate relationship between kinase inhibitors and AhR.Copyright © 2024. Published by Elsevier Inc.