Pharmaco-genomic investigations of organo-iridium anticancer complexes reveal novel mechanism of action

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(Cpxbiph)(ppy)Cl] (ZL49, 1, ppy=phenylpyridine) and [Ir(Cpxph)(azpyNMe2)Cl]PF6 (ZL109, 2, azpyNMe2=N,N-dimethylphenylazopyridine) in 916 cancer cell lines from 28 tissue types. On average, complex 2 was 78x more potent than 1, 36x 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.