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Discovery of Novel Pyrrolo[2,3-d]pyrimidine-based Derivatives as Potent JAK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors

文献类型：期刊论文

作者Liang, Xuewu2; Tang, Shuai2; Liu, Xuyi2; Liu, Yingluo2; Xu, Qifu1; Wang, Xiaomin2; Saidahmatov, Abdusaid2; Li, Chunpu2; Wang, Jiang2; Zhou, Yu2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-01-27
卷号65期号:2页码:1243-1264
ISSN号0022-2623
DOI10.1021/acs.jmedchem.0c02111
通讯作者Huang, Min(mhuang@simm.ac.cn) ; Liu, Hong(hliu@mail.shcnc.ac.cn)
英文摘要It remains a big challenge to develop HDAC inhibitors effective for solid tumors. Previous studies have suggested that the feedback activation of JAK-STAT3 pathway represents a key mechanism leading to resistance to HDAC inhibitors in breast cancer, suggesting the therapeutic promise of JAK/HDAC dual inhibitors. In this work, we discovered a series of pyrrolo[2,3-d]pyrimidine-based derivatives as potent JAK and HDAC dual inhibitors. Especially, compounds 15d and 15h potently inhibited JAK1/2/3 and HDAC1/6 and displayed antiproliferative and proapoptotic activities in triple-negative breast cancer cell lines. Besides, compounds 15d and 15h also diminished the activation of LIFR-JAK-STAT signaling triggered by tumor-associated fibroblasts, which suggests that these compounds could potentially overcome the drug resistance caused by the tumor microenvironment. More importantly, compound 15d effectively inhibited the tumor growth in MDA-MB-231 xenograft tumor model. Overall, this work provides valuable leads and novel antitumor mechanisms for the treatment of the SAHA-resistant triple-negative breast cancers.
WOS关键词HISTONE DEACETYLASE INHIBITORS ; JANUS KINASES JAKS ; PHASE-II ; SIGNAL TRANSDUCERS ; DESIGN ; ROMIDEPSIN ; ACTIVATORS ; LEUKEMIA ; TRIAL
资助项目National Natural Science Foundation of China[21907102] ; National Natural Science Foundation of China[21632008] ; National Natural Science Foundation of China[91229204] ; National Natural Science Foundation of China[81473245] ; National Natural Science Foundation of China[81772695]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000766751000013
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/300191]  
专题新药研究国家重点实验室
通讯作者Huang, Min; Liu, Hong
作者单位1.Shandong Univ, Sch Pharm, Dept Med Chem, Jinan 250012, Shandong, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Liang, Xuewu,Tang, Shuai,Liu, Xuyi,et al. Discovery of Novel Pyrrolo[2,3-d]pyrimidine-based Derivatives as Potent JAK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(2):1243-1264.
APA Liang, Xuewu.,Tang, Shuai.,Liu, Xuyi.,Liu, Yingluo.,Xu, Qifu.,...&Liu, Hong.(2022).Discovery of Novel Pyrrolo[2,3-d]pyrimidine-based Derivatives as Potent JAK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors.JOURNAL OF MEDICINAL CHEMISTRY,65(2),1243-1264.
MLA Liang, Xuewu,et al."Discovery of Novel Pyrrolo[2,3-d]pyrimidine-based Derivatives as Potent JAK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors".JOURNAL OF MEDICINAL CHEMISTRY 65.2(2022):1243-1264.

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来源：上海药物研究所

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