Discovery of Janus Kinase 2 (JAK2) and Histone Deacetylase (HDAC) Dual Inhibitors as a Novel Strategy for the Combinational Treatment of Leukemia and Invasive Fungal Infections
Discovery of Janus Kinase 2 (JAK2) and Histone Deacetylase (HDAC) Dual Inhibitors as a Novel Strategy for the Combinational Treatment of Leukemia and Invasive Fungal Infections
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DOI：
10.1021/acs.jmedchem.8b00393
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发表时间：
2018-07-26
影响因子：
7.3
通讯作者：
Sheng, Chunquan
中科院分区：
文献类型：
--
作者：
Huang, Yahui;Dong, Guoqiang;Sheng, Chunquan
针对临床上白血病患者化疗效果有限且易被侵袭性真菌感染的问题，提出了一种小分子药物同时治疗白血病和侵袭性真菌感染的新策略。新发现的JAK2和组蛋白脱乙酰酶(HDAC)双抑制剂对血液学细胞株具有很强的抗增殖活性，与氟康唑具有良好的协同作用。尤其是化合物20a，它是一种高活性和选择性的JAK2/HDAC6双重抑制剂，在几种急性髓系白血病(AML)模型中显示出出色的体内抗肿瘤效果，并与氟康唑协同治疗耐药的白色念珠菌感染。这项研究强调了JAK2/HDAC双重抑制剂在治疗AML和IFIS方面的治疗潜力，并为多靶点药物开发提供了一种有效的策略。
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.