Antagonizing STAT3 dimerization with a rhodium(III) complex.

Abstract

Kinetically inert metal complexes have arisen as promising alternatives to existing platinum and ruthenium chemotherapeutics. Reported herein, to our knowledge, is the first example of a substitutionally inert, Group 9 organometallic compound as a direct inhibitor of signal transducer and activator of transcription 3 (STAT3) dimerization. From a series of cyclometalated rhodium(III) and iridium(III) complexes, a rhodium(III) complex emerged as a potent inhibitor of STAT3 that targeted the SH2 domain and inhibited STAT3 phosphorylation and dimerization. Significantly, the complex exhibited potent anti-tumor activities in an in vivo mouse xenograft model of melanoma. This study demonstrates that rhodium complexes may be developed as effective STAT3 inhibitors with potent anti-tumor activity.

• Authors: Dik-Lung Ma, Li-Juan Liu, Ka-Ho Leung, Yen-Ting Chen, Hai-Jing Zhong, Daniel Shiu-Hin Chan, Hui-Min David Wang, Chung-Hang Leung
• Journal: Angewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Vol. 53 Issue 35 Pg. 9178-82 (Aug 25 2014) ISSN: 1521-3773 [Electronic] Germany
• PMID: 24889897 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Organometallic Compounds
• STAT3 Transcription Factor
• STAT3 protein, human
• Rhodium

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Humans
• Melanoma (drug therapy, metabolism)
• Mice
• Molecular Structure
• Organometallic Compounds (chemical synthesis, chemistry, pharmacology)
• Phosphorylation (drug effects)
• Protein Binding (drug effects)
• Protein Multimerization (drug effects)
• Rhodium (chemistry)
• STAT3 Transcription Factor (chemistry, metabolism)
• Structure-Activity Relationship
• Xenograft Model Antitumor Assays