Clinically, leukemia patients often suffer from the limited efficacy of chemotherapy and high risks of infection by invasive fungal pathogens. Herein, a novel therapeutic strategy was developed in which a small molecule can simultaneously treat leukemia and invasive fungal infections (IFIs). Novel Janus kinase 2 (JAK2) and histone deacetylase (HDAC) dual inhibitors were identified to possess potent anti-proliferative activity toward hematological cell lines and excellent synergistic effects with fluconazole to treat resistant Candida albicans infections. In particular, compound 20a, a highly active and selective JAK2/HDAC6 dual inhibitor, showed excellent in vivo antitumor efficacy in several acute myeloid leukemia (AML) models and synergized with fluconazole for the treatment of resistant C. albicans infections. This study highlights the therapeutic potential of JAK2/HDAC dual inhibitors in treating AML and IFIs and provides an efficient strategy for multitargeting drug discovery.

中文翻译：

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发现Janus激酶2（JAK2）和组蛋白去乙酰化酶（HDAC）双重抑制剂是白血病和浸润性真菌感染联合治疗的新策略

在临床上，白血病患者经常遭受化学疗法的功效有限和侵入性真菌病原体感染的高风险。本文中，开发了一种新颖的治疗策略，其中小分子可以同时治疗白血病和侵袭性真菌感染（IFI）。新型Janus激酶2（JAK2）和组蛋白脱乙酰基酶（HDAC）双重抑制剂经鉴定对血液细胞系具有有效的抗增殖活性，并与氟康唑具有出色的协同作用，可治疗白色念珠菌感染。特别是化合物20a，一种高活性和选择性的JAK2 / HDAC6双重抑制剂，在几种急性髓样白血病（AML）模型中显示出优异的体内抗肿瘤功效，并与氟康唑协同治疗耐药性白色念珠菌感染。这项研究突出了JAK2 / HDAC双重抑制剂在治疗AML和IFI中的治疗潜力，并为多靶点药物发现提供了有效的策略。