Inhibition of the Ras/Raf interaction and repression of renal cancer xenografts in vivo by an enantiomeric iridium( iii ) metal-based compound
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...
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| Published in | Chemical science (Cambridge) Vol. 8; no. 7; pp. 4756 - 4763 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Royal Society of Chemistry
01.07.2017
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 2041-6520 2041-6539 2041-6539 |
| DOI | 10.1039/C7SC00311K |
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| 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. |
|---|---|
| AbstractList | 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 Delta -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. 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. 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 exhibited potent inhibitory activity against the H-Ras/Raf-1 interaction and its signaling pathway and , and also directly engaged both H-Ras and Raf-1-RBD in cell lysates. Moreover, repressed tumor growth in a mouse renal xenograft tumor model. Intriguingly, the -enantiomer of showed superior potency in the biological assays compared to or racemic . 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. This study reports the first use of an iridium(iii) compound and its enantiomer to inhibit the H-Ras/Raf-I PPI in vitro and repress renal cancer xenografts in vivo. 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. 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.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. |
| Author | Tian, Jinglin Lin, Sheng Ma, Dik-Lung Wang, Wanhe Cai, Zongwei Huang, Shi-Ying Liu, Li-Juan Hong, Yanjun Li, Guodong Leung, Chung-Hang Wang, Hui-Min David |
| AuthorAffiliation | b Department of Chemistry , Hong Kong Baptist University , Kowloon Tong , Hong Kong , China . Email: edmondma@hkbu.edu.hk f Graduate Institute of Biomedical Engineering , National Chung Hsing University , Taichung 402 , Taiwan . Email: davidw@dragon.nchu.edu.tw c College of Oceanology and Food Science , Quanzhou Normal University , Quanzhou 362000 , China d Key Laboratory for the Development of Bioactive Material from Marine Algae , Quanzhou 362000 , China e Partner State Key Laboratory of Environmental and Biological Analysis , Department of Chemistry , Hong Kong Baptist University , 224 Waterloo Road , Kowloon Tong , Hong Kong SAR , P. R. China . Email: zwcai@hkbu.edu.hk a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences , University of Macau , Macao , China . Email: duncanleung@umac.mo |
| AuthorAffiliation_xml | – name: b Department of Chemistry , Hong Kong Baptist University , Kowloon Tong , Hong Kong , China . Email: edmondma@hkbu.edu.hk – name: e Partner State Key Laboratory of Environmental and Biological Analysis , Department of Chemistry , Hong Kong Baptist University , 224 Waterloo Road , Kowloon Tong , Hong Kong SAR , P. R. China . Email: zwcai@hkbu.edu.hk – name: a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences , University of Macau , Macao , China . Email: duncanleung@umac.mo – name: d Key Laboratory for the Development of Bioactive Material from Marine Algae , Quanzhou 362000 , China – name: f Graduate Institute of Biomedical Engineering , National Chung Hsing University , Taichung 402 , Taiwan . Email: davidw@dragon.nchu.edu.tw – name: c College of Oceanology and Food Science , Quanzhou Normal University , Quanzhou 362000 , China |
| Author_xml | – sequence: 1 givenname: Li-Juan surname: Liu fullname: Liu, Li-Juan organization: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China – sequence: 2 givenname: Wanhe surname: Wang fullname: Wang, Wanhe organization: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, China – sequence: 3 givenname: Shi-Ying surname: Huang fullname: Huang, Shi-Ying organization: College of Oceanology and Food Science, Quanzhou Normal University, Quanzhou 362000, China, Key Laboratory for the Development of Bioactive Material from Marine Algae – sequence: 4 givenname: Yanjun surname: Hong fullname: Hong, Yanjun organization: Partner State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, P. R. China – sequence: 5 givenname: Guodong surname: Li fullname: Li, Guodong organization: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China – sequence: 6 givenname: Sheng surname: Lin fullname: Lin, Sheng organization: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, China – sequence: 7 givenname: Jinglin surname: Tian fullname: Tian, Jinglin organization: Partner State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, P. R. China – sequence: 8 givenname: Zongwei surname: Cai fullname: Cai, Zongwei organization: Partner State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, P. R. China – sequence: 9 givenname: Hui-Min David orcidid: 0000-0002-3407-9568 surname: Wang fullname: Wang, Hui-Min David organization: Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taiwan – sequence: 10 givenname: Dik-Lung surname: Ma fullname: Ma, Dik-Lung organization: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, China – sequence: 11 givenname: Chung-Hang orcidid: 0000-0003-2988-3786 surname: Leung fullname: Leung, Chung-Hang organization: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28959398$$D View this record in MEDLINE/PubMed |
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| Snippet | Targeting protein–protein interactions (PPIs) offers tantalizing opportunities for therapeutic intervention for the treatment of human diseases. Modulating PPI... Targeting protein-protein interactions (PPIs) offers tantalizing opportunities for therapeutic intervention for the treatment of human diseases. Modulating PPI... This study reports the first use of an iridium(iii) compound and its enantiomer to inhibit the H-Ras/Raf-I PPI in vitro and repress renal cancer xenografts in... |
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| SubjectTerms | Arrays Cancer Chemistry Diseases Inhibitors Lead (metal) Medical services Scaffolds Tumors |
| Title | Inhibition of the Ras/Raf interaction and repression of renal cancer xenografts in vivo by an enantiomeric iridium( iii ) metal-based compound |
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