Background/Objectives: Acute myeloid leukemia (AML) is characterized by therapeutic failure and long-term risk for disease relapses. As several therapeutic targets participate in networks, they can rewire to eventually evade single-target drugs. Hence, multi-targeting approaches are considered on the expectation that interference with many different components could synergistically hinder activation of alternative pathways and demolish the network one-off, leading to complete disease remission. Methods: Herein, we established a network-based, computer-aided approach for the rational design of drug combinations and de novo agents that interact with many AML network components simultaneously. Results: A reconstructed AML network guided the selection of suitable protein hubs and corresponding multi-targeting strategies. For proteins responsive to existing drugs, a greedy algorithm identified the minimum amount of compounds targeting the maximum number of hubs. We predicted permissible combinations of amiodarone, artenimol, fostamatinib, ponatinib, procaine, and vismodegib that interfere with 3–8 hubs, and we elucidated the pharmacological mode of action of procaine on DNMT3A. For proteins that do not respond to any approved drugs, namely cyclins A1, D2, and E1, we used structure-based de novo drug design to generate a novel triple-targeting compound of the chemical formula C15H15NO5, with favorable pharmacological and drug-like properties. Conclusions: Overall, by integrating network and structural pharmacology with molecular modeling, we determined two complementary strategies with the potential to annihilate the AML network, one in the form of repurposable drug combinations and the other as a de novo synthesized triple-targeting agent. These target–drug interactions could be prioritized for preclinical and clinical testing toward precision medicine for AML.
背景/目的：急性髓系白血病（AML）以治疗失败和长期复发风险为特征。由于多个治疗靶点参与网络调控，这些靶点可能通过重编程机制逃避单一靶点药物的作用。因此，多靶点治疗策略被寄予厚望，期望通过同时干扰多个网络组分，协同阻断替代通路的激活，从而一次性摧毁疾病网络，实现完全缓解。方法：本研究建立了一种基于网络的计算辅助方法，用于合理设计能同时作用于AML网络多个组分的药物组合及全新药物。结果：通过重建AML网络，筛选出关键蛋白枢纽并制定相应多靶点策略。针对已有药物可作用的靶点，采用贪心算法确定了以最少化合物覆盖最多枢纽的最优方案。我们预测了胺碘酮、青蒿琥酯、福斯塔替尼、普纳替尼、普鲁卡因和维莫德吉的可行组合方案，这些药物可干扰3-8个枢纽靶点，并阐明了普鲁卡因对DNMT3A的药理作用机制。针对尚无获批药物的靶点（细胞周期蛋白A1、D2和E1），采用基于结构的全新药物设计方法，成功开发出化学式为C15H15NO5的新型三靶点化合物，该化合物具有良好的药理学特性及类药性。结论：本研究通过整合网络药理学、结构药理学与分子建模技术，确立了两种具有互补潜力的AML网络干预策略：一是基于现有药物的再定位组合方案，二是全新设计的三靶点合成化合物。这些靶点-药物相互作用机制可为AML精准医疗的临床前及临床研究提供优先研究方向。
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