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Discovery of CZL-046 with an (S)-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma

文献类型：期刊论文

作者Chen, Zonglong8; Yang, Hong7; Zhang, Yan6; Lyu, Xiaodong8; Shi, Qiongyu7; Zhang, Cheng6; Wang, Xingcan5; Wang, Zekun5; Zhang, Ying4,7; Deng, Yue5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-10-02
卷号67期号:20页码:18606-18628
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c01984
通讯作者Xu, Yong(xu_yong@gibh.ac.cn) ; Huang, Xun(xhuang@lglab.ac.cn) ; Li, Yingxia(liyx417@fudan.edu.cn)
英文摘要E1A binding protein (p300) is a promising therapeutic target for the treatment of cancer. Herein, we report the discovery of a series of novel inhibitors with an (S)-3-fluoropyrrolidin-2-one scaffold targeting p300 bromodomain. The best compound 29 (CZL-046) shows potent inhibitory activity of p300 bromodomain (IC50 = 3.3 nM) and antiproliferative activity in the multiple myeloma (MM) cell line (OPM-2 IC50 = 51.5 nM). 29 suppressed the mRNA levels of c-Myc and IRF4 and downregulated the expression of c-Myc and H3K27Ac. Compared to the lead compound 5, 29 exhibits significantly improved in vitro and in vivo metabolic properties. Oral administration of 29 with 30 mg/kg achieved a TGI value of 44% in the OPM-2 xenograft model, accompanied by good tolerability. The cocrystal structure of CREB binding protein bromodomain with 29 provides an insight into the precise binding mode. The results demonstrate that 29 is a promising p300 bromodomain inhibitor for the treatment of MM.
WOS关键词POTENT ; PROTEIN ; CBP ; ACETYLATION ; DERIVATIVES ; SYSTEM
资助项目Qingdao Marine Science and Technology Pilot National Laboratory Shandong Provincial Special Fund[2022QNLM030003-2] ; General Program of National Natural Science Foundation of China[82173835] ; Program of Shanghai Subject Chief Scientist[22XD1425300] ; Major projects of National Natural Science Foundation of China[81991523] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2019CXJQ02] ; SA-SIBS Scholarship Program ; Shanghai Municipal Science and Technology Major Project ; National Key R&D Program of China[2022YFE0210600] ; Guangdong Province Grant for Belt and Road Joint Laboratory[2022A0505090006]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001327102900001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/313684]  
专题新药研究国家重点实验室
通讯作者Xu, Yong; Huang, Xun; Li, Yingxia
作者单位1.Fudan Univ, Huashan Hosp, Shanghai Med Coll, Natl Med Ctr Infect Dis,Dept Infect Dis,Shanghai K, Shanghai 200040, Peoples R China
2.Nanjing Univ Chinese Med, Sch Med & Holist Integrat Med, Nanjing 210023, Jiangsu, Peoples R China
3.Shanghai Jiao Tong Univ, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, Inst Drug Discovery, Guangzhou Inst Biomed & Hlth, China New Zealand Joint Lab Biomed & Hlth,State Ke, Guangzhou 510530, Peoples R China
7.Lingang Lab, Shanghai 200031, Peoples R China
8.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Zonglong,Yang, Hong,Zhang, Yan,et al. Discovery of CZL-046 with an (S)-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(20):18606-18628.
APA Chen, Zonglong.,Yang, Hong.,Zhang, Yan.,Lyu, Xiaodong.,Shi, Qiongyu.,...&Li, Yingxia.(2024).Discovery of CZL-046 with an (S)-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma.JOURNAL OF MEDICINAL CHEMISTRY,67(20),18606-18628.
MLA Chen, Zonglong,et al."Discovery of CZL-046 with an (S)-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma".JOURNAL OF MEDICINAL CHEMISTRY 67.20(2024):18606-18628.

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来源：上海药物研究所

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