Inhibition of the Ras/Raf interaction and repression of renal cancer xenografts in vivo by an enantiomeric iridium(III) metal-based compound

Li Juan Liu, Wanhe Wang, Shi Ying Huang, Yanjun HONG, Guodong Li, Sheng Lin, Jinglin Tian, Zongwei CAI*, Hui Min David Wang, Edmond Dik Lung MA, Chung Hang Leung

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

89 Citations (Scopus)

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 Δ-enantiomer of 1 showed superior potency in the biological assays compared to Λ-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.

Original languageEnglish
Pages (from-to)4756-4763
Number of pages8
JournalChemical Science
Volume8
Issue number7
DOIs
Publication statusPublished - 2017

Scopus Subject Areas

  • Chemistry(all)

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