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Development of a First-in-Class DNMT1/HDAC Inhibitor with Improved Therapeutic Potential and Potentiated Antitumor Immunity

文献类型：期刊论文

作者Chang, Yingjie5; Guo, Huahui3,4; Li, Xue5; Zong, Liangyi3,4; Wei, Jiale2; Li, Zhihai2; Luo, Cheng1,2; Yang, Xinying5; Fang, Hao5; Kong, Xiangqian3,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-09-12
卷号67期号:18页码:16480-16504
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c01310
通讯作者Kong, Xiangqian(kong_xiangqian@gibh.ac.cn) ; Hou, Xuben(hxb@sdu.edu.cn)
英文摘要Epigenetic therapies have emerged as a key paradigm for treating malignancies. In this study, a series of DNMT1/HDAC dual inhibitors were obtained by fusing the key pharmacophores from DNMT1 inhibitors (DNMT1i) and HDAC inhibitors (HDACi). Among them, compound (R)-23a demonstrated significant DNMT1 and HDAC inhibition both in vitro and in cells and largely phenocopied the synergistic effects of combined DNMT1i and HDACi in reactivating epigenetically silenced tumor suppressor genes (TSGs). This translated into a profound tumor growth inhibition (TGI = 98%) of (R)-23a in an MV-4-11 xenograft model, while displaying improved tolerability compared with single agent combination. Moreover, in a syngeneic MC38 mouse colorectal tumor model, (R)-23a outperformed the combinatory treatment in reshaping the tumor immune microenvironment and inducing tumor regression. Collectively, the novel DNMT1/HDAC dual inhibitor (R)-23a effectively reverses the cancer-specific epigenetic abnormalities and holds great potential for further development into cancer therapeutic agents.
WOS关键词HISTONE DEACETYLASE INHIBITION ; DNA METHYLTRANSFERASE 1 ; EPIGENETIC THERAPY ; TUMOR-SUPPRESSOR ; CANCER EPIGENOME ; IN-VIVO ; METHYLATION ; GENES ; INACTIVATION ; HALLMARKS
资助项目National Natural Science Foundation of China[81874288] ; National Natural Science Foundation of China[22377068] ; National Natural Science Foundation of China[22107101] ; Taishan Scholar Programme of Shandong Province[tstp.20230606] ; Shandong Provincial Youth Innovation Team Development Program[2023KJ026] ; Young Scholars Program of Shandong University ; Guangdong Basic and Applied Basic Research Foundation[2021B1515420002] ; Pearl River Talents Plan[2021QN02Y734] ; Lingang Laboratory[LG-QS-202205-07] ; National Key Research and Development Program of China[2022YFC3400500] ; National Key Research and Development Program of China[2021ZD0203900] ; National Key Research and Development Program of China[2023YFD1800102] ; National Key Research and Development Program of China[2022YFC2804800] ; Basic Research Project of Guangzhou Institutes of Biomedicine and Health[GIBHBRP23-03] ; Basic Research Project of Guangzhou Institutes of Biomedicine and Health[GIBHBRP24-04]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001310821800001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/313359]  
专题新药研究国家重点实验室
通讯作者Kong, Xiangqian; Hou, Xuben
作者单位1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Univ Chinese Acad Sci UCAS, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangdong Prov Key Lab Stem Cell & Regenerat Med, State Key Lab Resp Dis,China New Zealand Joint Lab, Guangzhou 510530, Peoples R China
5.Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Key Lab Chem Biol,Minist Educ, Jinan 250012, Peoples R China
推荐引用方式
GB/T 7714		 Chang, Yingjie,Guo, Huahui,Li, Xue,et al. Development of a First-in-Class DNMT1/HDAC Inhibitor with Improved Therapeutic Potential and Potentiated Antitumor Immunity[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(18):16480-16504.
APA Chang, Yingjie.,Guo, Huahui.,Li, Xue.,Zong, Liangyi.,Wei, Jiale.,...&Hou, Xuben.(2024).Development of a First-in-Class DNMT1/HDAC Inhibitor with Improved Therapeutic Potential and Potentiated Antitumor Immunity.JOURNAL OF MEDICINAL CHEMISTRY,67(18),16480-16504.
MLA Chang, Yingjie,et al."Development of a First-in-Class DNMT1/HDAC Inhibitor with Improved Therapeutic Potential and Potentiated Antitumor Immunity".JOURNAL OF MEDICINAL CHEMISTRY 67.18(2024):16480-16504.

入库方式： OAI收割

来源：上海药物研究所

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