Discovery of Novel Macrocyclic Hedgehog Pathway Inhibitors Acting by Suppressing the Gli-Mediated Transcription

doi:10.1021/acs.jmedchem.7b01185

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	Discovery of Novel Macrocyclic Hedgehog Pathway Inhibitors Acting by Suppressing the Gli-Mediated Transcription
	Liu, Gang 1,2,3; Huang, Wenjing 4; Wang, Juan 4; Liu, Xiaohua 2,3; Yang, Jun 4; Zhang, Yu 4; Geng, Yong1,2,3 ; Tan, Wenfu 4; Zhang, Ao1,2,3,5
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2017-10-12
卷号	60 期号:19 页码:8218-8245
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.7b01185
文献子类	Article
英文摘要	[GRAPHICS] A systemic medicinal chemistry campaign was conducted based on a literature hit compound 5 bearing the 4,5-dihydro-2H-benzo[b][1,5]oxazocin-6(3H)-one core through cyclization of two side substituents of the bicyclic skeleton combined with N-atom walking or ring walking and the central ring expansion or extraction approaches, leading to several series of structurally unique tricyclic compounds. Among these, compound 29a was identified as the most potent against the Hedgehog (Hh) signaling pathway showing an IC50 value of 23 nM. Mechanism studies indicated that compound 29a inhibited the Hh signaling pathway by suppressing the expression of the transcriptional factors Gli rather than by interrupting the binding of Gli with DNA. We further observed that 29a was equally potent against both Smo wild type and the two major resistant mutants (Smo D473H and Smo W535L). It potently inhibited the proliferation of medulloblastoma cells and showed significant tumor growth inhibition in the ptch +/- ;p53-/- medulloblastoma allograft mice model. Though more studies are needed to clarify the precise interaction pattern of 29a with Gli, its promising in vitro and in vivo properties encourage further profiling as a new generation Hh signaling inhibitor to treat tumors primarily or secondarily resistant to current Smo inhibitors.
资助项目	Chinese NSF[81773565] ; Chinese NSF[81773767] ; Chinese NSF[81430080] ; National Program on Key Basic Research Project of China[2015CB910603-004] ; International Cooperative Program[GJHZ1622] ; Frontier Science of the Chinese Academy of Sciences[160621] ; Shanghai Commission of Science and Technology[16XD1404600] ; Shanghai Commission of Science and Technology[14431900400] ; CAS Key Laboratory of Receptor Research of SIMM[SIMM1606YKF-08] ; CAS Key Laboratory of Receptor Research of SIMM[SIMM1606YZZ-06]
WOS关键词	BASAL-CELL CARCINOMA ; CANCER ; MEDULLOBLASTOMA ; GROWTH ; ACTIVATION ; RESISTANCE ; VISMODEGIB ; ANTAGONISTS ; SONIDEGIB ; STRATEGY
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000413131400020
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272454]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物化学研究室
通讯作者	Tan, Wenfu; Zhang, Ao
作者单位	1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.SIMM, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 3.SIMM, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Fudan Univ, Dept Pharmacol, Sch Pharm, Shanghai 201203, Peoples R China; 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China;
推荐引用方式 GB/T 7714	Liu, Gang,Huang, Wenjing,Wang, Juan,et al. Discovery of Novel Macrocyclic Hedgehog Pathway Inhibitors Acting by Suppressing the Gli-Mediated Transcription[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(19):8218-8245.
APA	Liu, Gang.,Huang, Wenjing.,Wang, Juan.,Liu, Xiaohua.,Yang, Jun.,...&Zhang, Ao.(2017).Discovery of Novel Macrocyclic Hedgehog Pathway Inhibitors Acting by Suppressing the Gli-Mediated Transcription.JOURNAL OF MEDICINAL CHEMISTRY,60(19),8218-8245.
MLA	Liu, Gang,et al."Discovery of Novel Macrocyclic Hedgehog Pathway Inhibitors Acting by Suppressing the Gli-Mediated Transcription".JOURNAL OF MEDICINAL CHEMISTRY 60.19(2017):8218-8245.