Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein-Protein Interactions

doi:10.1021/acs.jmedchem.1c00940

	Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein-Protein Interactions
	Zhang, Shiyan 1,2,3; Lou, Jianfeng 1,2,3; Li, Yafang 2,3,4; Zhou, Feilong 2,3; Yan, Ziqin 2,3; Lyu, Xilin 2,3; Zhao, Yujun 1,2,3,5
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-08-12
卷号	64 期号:15 页码:10621-10640
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.1c00940
通讯作者	Zhao, Yujun(yjzhao@simm.ac.cn)
英文摘要	MDM4 is a homologue of MDM2, serving cooperatively as the negative regulator of tumor suppressor p53. Under the shadow of MDM2 inhibitors, limited efforts had been put into the discovery of MDM4 modulators. Recent studies of the experimental drug ALRN-6924, a dual MDM4 and MDM2 inhibitor, suggest that concurrent inhibition of MDM4 and MDM2 might be beneficial over only MDM2 inhibition. In view of the present research progress, we summarized published inhibitors of MDM4/p53 interactions including both peptide-based compounds and small molecules. Cocrystal structures of ligand/ MDM4 complexes have been examined, and their structural features were compiled and compared in order to show the molecular basis required for high MDM4 binding affinities. Representative examples of small-molecule MDM4 inhibitors were discussed, followed by clinical results of ALRN-6924, together, providing a consolidated reference for further development of MDM4 inhibitors, either dual or selective.
资助项目	National Natural Science Foundation of China[82073682] ; National Natural Science Foundation of China[81872724] ; National Major Science & Technology Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-004-010] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; K. C. Wong Education Foundation
WOS关键词	HDMX-MEDIATED SUPPRESSION ; DOUBLE MINUTE 2 ; SMALL-MOLECULE ; P53 PATHWAY ; HUMAN MDM2 ; STAPLED P53 ; DISCOVERY ; POTENT ; IDENTIFICATION ; ACTIVATION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000685644300008
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297654]
专题	中国科学院上海药物研究所
通讯作者	Zhao, Yujun
作者单位	1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Small Mol Drug Res Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 4.Univ Sci & Technol China, Nano Sci & Technol Inst, Suzhou 215123, Jiangsu, Peoples R China 5.Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou 450001, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Shiyan,Lou, Jianfeng,Li, Yafang,et al. Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein-Protein Interactions[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(15):10621-10640.
APA	Zhang, Shiyan.,Lou, Jianfeng.,Li, Yafang.,Zhou, Feilong.,Yan, Ziqin.,...&Zhao, Yujun.(2021).Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein-Protein Interactions.JOURNAL OF MEDICINAL CHEMISTRY,64(15),10621-10640.
MLA	Zhang, Shiyan,et al."Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein-Protein Interactions".JOURNAL OF MEDICINAL CHEMISTRY 64.15(2021):10621-10640.