Antagonizing STAT3 Dimerization with a Rhodium(III) Complex

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. Saving your skin: A rhodium(III) complex is the first example of a substitutionally inert, Group 9 organometallic compound which serves as a direct inhibitor of the signal transducer and activator of transcription 3 (STAT3) dimerization. The rhodium(III) complex inhibited STAT3 activity in vitro and in vivo and showed potent and selective anticancer activity against melanoma cell lines and melanoma xenografts in an in vivo mouse model.