Synthesis and Evaluation of 3-(Indol-3-yl)-4-(Pyrazolo[3,4-c]Pyridazin-3-yl)-Maleimides as Potent Mutant Isocitrate Dehydrogenase-1 Inhibitors

doi:10.1007/s11094-021-02475-0

	Synthesis and Evaluation of 3-(Indol-3-yl)-4-(Pyrazolo[3,4-c]Pyridazin-3-yl)-Maleimides as Potent Mutant Isocitrate Dehydrogenase-1 Inhibitors
	Xu, Jianghong 2; Hu, Yuanyuan 2; Liu, Xiaoqi 2; Gao, Anhui 1; Gao, Lixin 1; Xu, Lei 1; Zhou, Yubo 1; Gao, Jianrong 2; Ye, Qing 2; Hu, Chunqi 3
刊名	PHARMACEUTICAL CHEMISTRY JOURNAL
	2021-10-01
卷号	55 期号:7 页码:655-664
关键词	IDH1-R132H inhibitors synthesis biological activity docking 3-(indol-3-yl)-4-(pyrazolo-[3 4-c]pyridazin-3-yl)-maleimides
ISSN号	0091-150X
DOI	10.1007/s11094-021-02475-0
通讯作者	Ye, Qing(yeqing1975@zjut.edu.cn)
英文摘要	A series of new 3-(indol-3-yl)-4-(pyrazolo[3,4-c]pyridazin-3-yl)-maleimides were synthesized and evaluated for their inhibitory activity against IDH1-R132H. Most compounds exhibited significant potency to IDH1-R132H inhibition. Among these, 3-(1-(3-(1H-imidazol-1-yl)propyl)-6-bromo-1H-indol-3-yl)-4-(1-methyl-1H-pyrazolo[3,4-c]pyridazin-3-yl)-1H-pyrrole-2,5-dione (compound IXb), was the most promising IDH1-R132H inhibitor (IC50 = 0.031 mu M) and could significantly inhibit the production of 2-HG in U87MG IDH1-R132H cells. Preliminary structure-activity relationships and molecular modeling studies are discussed based on the experimental data obtained.
资助项目	Natural Science Foundation of Zhejiang[LY18H300009] ; Postdoctoral Science Foundation of China[2014M550256] ; State Key Laboratory of Drug Research[SIMM1601KF-04] ; National Natural Science Foundation of China[8150131067] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020328]
WOS关键词	IDH2 MUTATIONS ; ONCOMETABOLITE 2-HYDROXYGLUTARATE ; MYELODYSPLASTIC SYNDROMES ; GLIOMA ; DISCOVERY
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	SPRINGER
WOS记录号	WOS:000710310300005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298329]
专题	中国科学院上海药物研究所
通讯作者	Ye, Qing
作者单位	1.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 2.Zhejiang Univ Technol, State Key Lab Breeding Base Green Chem Synth Tech, Hangzhou 310032, Peoples R China 3.Shaoxing Univ, Coll Chem & Chem Engn, Shaoxing, Peoples R China
推荐引用方式 GB/T 7714	Xu, Jianghong,Hu, Yuanyuan,Liu, Xiaoqi,et al. Synthesis and Evaluation of 3-(Indol-3-yl)-4-(Pyrazolo[3,4-c]Pyridazin-3-yl)-Maleimides as Potent Mutant Isocitrate Dehydrogenase-1 Inhibitors[J]. PHARMACEUTICAL CHEMISTRY JOURNAL,2021,55(7):655-664.
APA	Xu, Jianghong.,Hu, Yuanyuan.,Liu, Xiaoqi.,Gao, Anhui.,Gao, Lixin.,...&Li, Ji.(2021).Synthesis and Evaluation of 3-(Indol-3-yl)-4-(Pyrazolo[3,4-c]Pyridazin-3-yl)-Maleimides as Potent Mutant Isocitrate Dehydrogenase-1 Inhibitors.PHARMACEUTICAL CHEMISTRY JOURNAL,55(7),655-664.
MLA	Xu, Jianghong,et al."Synthesis and Evaluation of 3-(Indol-3-yl)-4-(Pyrazolo[3,4-c]Pyridazin-3-yl)-Maleimides as Potent Mutant Isocitrate Dehydrogenase-1 Inhibitors".PHARMACEUTICAL CHEMISTRY JOURNAL 55.7(2021):655-664.