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Inhibition of the Ras/Raf interaction and repression of renal cancer xenografts in vivo by an enantiomeric iridium(III) metal-based compound
Liu, Li-Juan1; Wang, Wanhe2; Huang, Shi-Ying3,4; Hong, Yanjun5; Li, Guodong1; Lin, Sheng2; Tian, Jinglin5; Cai, Zongwei5; Wang, Hui-Min David6; Ma, Dik-Lung2; Leung, Chung-Hang1
2017-07
Source PublicationCHEMICAL SCIENCE
ISSN2041-6520
Volume8Issue:7Pages:4756-4763
Abstract

Targeting protein-protein interactions (PPIs) offers tantalizing opportunities for therapeutic intervention for the treatment of human diseases. Modulating PPI interfaces with organic small molecules has been found to be exceptionally challenging, and few candidates have been successfully developed into clinical drugs. Meanwhile, the striking array of distinctive properties exhibited by metal compounds renders them attractive scaffolds for the development of bioactive leads. Here, we report the identification of iridium(III) compounds as inhibitors of the H-Ras/Raf-1 PPI. The lead iridium(III) compound 1 exhibited potent inhibitory activity against the H-Ras/Raf-1 interaction and its signaling pathway in vitro and in vivo, and also directly engaged both H-Ras and Raf-1-RBD in cell lysates. Moreover, 1 repressed tumor growth in a mouse renal xenograft tumor model. Intriguingly, the (sic)-enantiomer of 1 showed superior potency in the biological assays compared to Lambda-1 or racemic 1. These compounds could potentially be used as starting scaffolds for the development of more potent Ras/Raf PPI inhibitors for the treatment of kidney cancer or other proliferative diseases.

DOI10.1039/c7sc00311k
URLView the original
Indexed BySCI
Language英语
WOS Research AreaChemistry
WOS SubjectChemistry, Multidisciplinary
WOS IDWOS:000404617300007
PublisherROYAL SOC CHEMISTRY
The Source to ArticleWOS
Fulltext Access
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Cited Times [WOS]:50   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorCai, Zongwei; Wang, Hui-Min David; Ma, Dik-Lung; Leung, Chung-Hang
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
2.Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, China
3.College of Oceanology and Food Science, Quanzhou Normal University, Quanzhou 362000, China
4.Key Laboratory for the Development of Bioactive Material from Marine Algae, Quanzhou 362000, China
5.Partner State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, 224 Waterloo Road, Kowloon Tong, P. R. China
6.Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung 402, Taiwan
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Liu, Li-Juan,Wang, Wanhe,Huang, Shi-Ying,et al. Inhibition of the Ras/Raf interaction and repression of renal cancer xenografts in vivo by an enantiomeric iridium(III) metal-based compound[J]. CHEMICAL SCIENCE,2017,8(7):4756-4763.
APA Liu, Li-Juan.,Wang, Wanhe.,Huang, Shi-Ying.,Hong, Yanjun.,Li, Guodong.,...&Leung, Chung-Hang.(2017).Inhibition of the Ras/Raf interaction and repression of renal cancer xenografts in vivo by an enantiomeric iridium(III) metal-based compound.CHEMICAL SCIENCE,8(7),4756-4763.
MLA Liu, Li-Juan,et al."Inhibition of the Ras/Raf interaction and repression of renal cancer xenografts in vivo by an enantiomeric iridium(III) metal-based compound".CHEMICAL SCIENCE 8.7(2017):4756-4763.
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