Hajjo Rima, Sabbah Dima A, Alhaded Raghad, Alquabe'h Aye, Bardaweel Sanaa K
Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan.
Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Pharmaceuticals (Basel). 2025 Jun 20;18(7):936. doi: 10.3390/ph18070936.
BCR-ABL inhibitors such as imatinib and nilotinib exhibit multi-kinase activity that extends beyond oncology, offering significant potential for drug repurposing. This study aims to systematically evaluate and prioritize the repurposing potential of BCR-ABL inhibitors, particularly imatinib and nilotinib. An integrated pharmacoinformatics framework was applied to analyze seven BCR-ABL inhibitors. Structural clustering, cheminformatics analysis, and transcriptomic profiling using the Connectivity Map were employed to evaluate structural relationships, target profiles, and gene expression signatures associated with non-oncology indications. Structurally, imatinib and nilotinib clustered closely, while HY-11007 exhibited distinct features. Nilotinib's high selectivity correlated with strong transcriptional effects in neurodegeneration-related pathways (e.g., HSP90 and LYN), whereas imatinib's broader kinase profile (PDGFR and c-KIT) was linked to fibrosis and metabolic regulation. Connectivity Map analysis identified more than 30 non-cancer indications, including known off-target uses (e.g., imatinib for pulmonary hypertension) and novel hypotheses (e.g., nilotinib for Alzheimer's via HSPA5 modulation). A substantial portion of these predictions aligned with the existing literature, underscoring the translational relevance of the approach. These findings highlight the importance of integrating structure-activity relationships and transcriptomic signatures to guide rational repurposing. We propose prioritizing nilotinib for CNS disorders and imatinib for systemic fibrotic diseases, supporting their advancement into preclinical and clinical evaluation. More broadly, this framework offers a versatile platform for uncovering hidden therapeutic potential across other drug classes with complex polypharmacology.
伊马替尼和尼洛替尼等BCR-ABL抑制剂具有超出肿瘤学领域的多激酶活性，为药物重新利用提供了巨大潜力。本研究旨在系统评估BCR-ABL抑制剂，特别是伊马替尼和尼洛替尼的重新利用潜力，并对其进行优先级排序。应用综合药物信息学框架分析了七种BCR-ABL抑制剂。采用结构聚类、化学信息学分析以及使用连通性图谱进行转录组分析，以评估与非肿瘤适应症相关的结构关系、靶点谱和基因表达特征。在结构上，伊马替尼和尼洛替尼聚类紧密，而HY-11007表现出独特特征。尼洛替尼的高选择性与神经退行性相关途径（如HSP90和LYN）中的强转录效应相关，而伊马替尼更广泛的激酶谱（PDGFR和c-KIT）与纤维化和代谢调节有关。连通性图谱分析确定了30多种非癌症适应症，包括已知的脱靶用途（如伊马替尼用于肺动脉高压）和新的假设（如尼洛替尼通过调节HSPA5用于治疗阿尔茨海默病）。这些预测中有很大一部分与现有文献一致，强调了该方法的转化相关性。这些发现突出了整合构效关系和转录组特征以指导合理重新利用的重要性。我们建议将尼洛替尼用于中枢神经系统疾病的优先级提高，将伊马替尼用于系统性纤维化疾病，支持它们进入临床前和临床评估。更广泛地说，该框架为揭示其他具有复杂多药理学特性的药物类别的潜在治疗价值提供了一个通用平台。
