The JMJD2 family enzymes (such as JMJD2D) rely on Fe­(II)/2-oxoglutarateto catalyze the demethylation of H3K9me3 and are abnormally activatedin cancer. Utilizing metal-chelatingscaffolds, we identified iridium­(III) complex 3 featuringtwo 1-phenylisoquinoline C∧N ligands and a 4,7-dmobpyN∧N ligand as a potent JMJD2D demethylase inhibitor.In contrast, the analogue complex bearing smaller 2-phenylpyridineC∧N ligands rather than the larger 1-phenylisoquinolineligands of complex 3 suggested that smaller C∧N ligands may not be as effective at disrupting the JMJD2D catalyticinterface. This evidence concerns the gene KDM4D and cancer.