Department of Chemistry
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.
Source Publication Title
Royal Society of Chemistry
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This work is supported by the Hong Kong Baptist University (FRG2/15-16/002), the Health and Medical Research Fund (HMRF/14130522), the Research Grants Council (HKBU/12301115, HKBU/204612, and HKBU/201913), the National Natural Science Foundation of China (21575121), the Guangdong Province Natural Science Foundation (2015A030313816), the Hong Kong Baptist University Century Club Sponsorship Scheme 2016, the Interdisciplinary Research Matching Scheme (RC-IRMS/15-16/03), the Science and Technology Development Fund, Macao SAR (098/2014/A2),the University of Macau (MYRG2015-00137-ICMS-QRCM, MYRG2016-00151-ICMS-QRCM and MRG044/LCH/2015/ICMS), the National Natural Science Foundation of China (21628502), and Ministry of Science and Technology (MOST 105-2622-E-005-006-CC2; MOST 104-2221-E-005-096-MY2; and MOST 104-2628-E-005-004-MY3). We thank Prof. Kazumasa Ohashi of the Department of Biomolecular Sciences, Graduate School of Life Sciences for the gifts of the BiFC plasmids.
Link to Publisher's Edition
Liu, L., Wang, W., Huang, S., Hong, Y., Li, G., Lin, S., Tian, J., Cai, Z., Wang, H., Ma, D., & Leung, C. (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. https://doi.org/10.1039/C7SC00311K