Pharmaco-genomic investigations of organo-iridium anticancer complexes reveal novel mechanism of actionElectronic supplementary information (ESI) available. See DOI: 10.1039/c7mt00242d

Resistance to platinum drugs (used in >50% of cancer chemotherapies) is a clinical problem. Other precious metal complexes with distinct mechanisms of action might overcome this. Half-sandwich organometallic complexes containing arene or cyclopentadienyl (Cp) ligands show promise. We screened two iridium( iii ) complexes [Ir(Cp Xbiph )(ppy)Cl] (ZL49, 1 , ppy = phenylpyridine) and [Ir(Cp Xph )(azpyNMe 2 )Cl]PF 6 (ZL109, 2 , azpyNMe 2 = N , N -dimethylphenylazopyridine) in 916 cancer cell lines from 28 tissue types. On average, complex 2 was 78× more potent than 1 , 36× more active than cisplatin (CDDP), and strongly active (nanomolar) in patient-derived ovarian cancer cell lines. RNA sequencing of A2780 ovarian cells revealed upregulation of antioxidant responses (NRF2, AP-1) consistent with observed induction of reactive oxygen species (ROS). Protein microarrays, high content imaging and cell cycle analysis showed S/G2 arrest, and late-stage DNA damage response without p53 requirement. The triple-negative breast cancer cell line OCUB-M was highly sensitive to 2 as were cell lines with KIT mutations. Complex 2 exhibits a markedly different pattern of antiproliferative activity compared to the 253 drugs in the Sanger Cancer Genome database, but is most similar to osmium( ii ) arene complexes which share the same azopyridine ligand. Redox modulation and DNA damage can provide a multi-targeting strategy, allowing compounds such as 2 to overcome cellular resistance to platinum anticancer drugs. Transcriptomic, phenotypic and high throughput data reveal unique anticancer mechanisms shared by organometallic iridium and osmium complexes.