Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies

doi:10.1021/acs.jmedchem.8b01597

	Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies
	Liang, Xuewu 1,4; Zang, Jie 1; Li, Xiaoyang 3; Tang, Shuai 4; Huang, Min 4; Geng, Meiyu 4; Chou, C. James 3; Li, Chunpu 4; Cao, Yichun 2; Xu, Wenfang 1
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2019-04-25
卷号	62 期号:8 页码:3898-3923
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.8b01597
通讯作者	Liu, Hong(hliu@mail.shcnc.ac.cn) ; Zhang, Yingjie(zhangyingjie@sdu.edu.cn)
英文摘要	Concurrent inhibition of Janus kinase (JAK) and histone deacetylase (HDAC) could potentially improve the efficacy of the HDAC inhibitors in the treatment of cancers and resolve the problem of HDAC inhibitor resistance in some tumors. Here, a novel series of pyrimidin-2-amino-pyrazol hydroxamate derivatives as JAK and HDAC dual inhibitors was designed, synthesized, and evaluated, among which 8m possessed potent and balanced activities against both JAK2 and HDAC6 with half-maximal inhibitory concentration at the nanomolar level. 8m exhibited improved antiproliferative and proapoptotic activities over SAHA and ruxolitinib in several hematological cell lines. Remarkably, 8m exhibited more potent antiproliferation effect than the combination of SAHA and ruxolitinib in HEL cells bearing JAK2(V617F) mutation. Pharmacokinetic studies in mice showed that 8m possessed good bioavailability after intraperitoneal administration. Finally, 8m showed antitumor efficacy with no significant toxicity in a HEL xenograft model. Collectively, the results confirm the therapeutic potential of JAK and HDAC dual inhibitors in hematological malignancies and provide valuable leads for further structural optimization and antitumor mechanism study.
资助项目	National High-Tech R&D Program of China (863 Program)[2014AA020523] ; Natural Science Foundation of Shandong Province[ZR2018QH007] ; Major Project of Science and Technology of Shandong Province[2017CXGC1401] ; Young Scholars Program of Shandong University (YSPSDU)[2016WLJH33]
WOS关键词	POLYCYTHEMIA-VERA ; MUTATION ; ACTIVATION ; GROWTH ; POLYPHARMACOLOGY ; MYELOFIBROSIS ; MECHANISMS ; CHALLENGES ; RESISTANCE ; DESIGN
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000466053900007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289905]
专题	中国科学院上海药物研究所
通讯作者	Liu, Hong; Zhang, Yingjie
作者单位	1.Shandong Univ, Sch Pharm, Dept Med Chem, Jinan 250012, Shandong, Peoples R China 2.Fudan Univ, Sch Pharm, 826 Zhanghen Rd, Shanghai 201203, Peoples R China 3.Med Univ South Carolina, Dept Drug Discovery & Biomed Sci, Coll Pharm, Charleston, SC 29425 USA 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Liang, Xuewu,Zang, Jie,Li, Xiaoyang,et al. Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(8):3898-3923.
APA	Liang, Xuewu.,Zang, Jie.,Li, Xiaoyang.,Tang, Shuai.,Huang, Min.,...&Zhang, Yingjie.(2019).Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies.JOURNAL OF MEDICINAL CHEMISTRY,62(8),3898-3923.
MLA	Liang, Xuewu,et al."Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies".JOURNAL OF MEDICINAL CHEMISTRY 62.8(2019):3898-3923.