Direct Targeting of Gene Regulators by Iridium(III) and Rhodium(III) Complexes

Aberrant gene expression is frequently linked to the progression of various disorders and diseases, playing an instrumental role in pathological processes. Gene-regulation-related proteins, especially epigenetic enzymes and transcription factors, are critically involved in gene expression patterns. Therefore, targeting endogenous gene regulators presents novel approaches for potential therapeutic intervention.Transition metal complexes have been extensively employed in diagnosis and treatment due to their distinctive properties. Organometallic iridium(III) and rhodium(III) complexes exhibit diverse structures, including photochemical and photophysical properties, kinetic stability, and the ability to interact specifically with biomolecules, particularly DNA and proteins, due to their selective steric engagement. Therefore, octahedral iridium(III) and rhodium(III) complexes represent attractive scaffolds for the design of probes and modulators of gene regulation.Considering the complexity and spatiotemporal specificity of gene regulation, it is crucial to comprehend the interactions between target biomolecules, particularly protein-protein interactions (PPIs), to selectively modulate gene expression patterns. PPIs serve as hubs of cellular signaling flow during most biological activities, including gene expression processes. For example, regulators of histone modifications and transcription factors converge at transcription start sites (TSSs), where they engage unmodified substrates and assemble into transcriptional complexes. Discovering and regulating disease-related abnormal gene expression by modulating pivotal PPIs thus hold great promise. By leveraging their precisely defined steric scaffolds, organometallic iridium(III) and rhodium(III) complexes present a distinctive option for unveiling the biological roles of these proteins and identifying potential modulators.In this Account, we discuss our recent work on discovering organometallic iridium(III) and rhodium(III) complexes for PPI-based gene modulation. First, we describe the interactions between these complexes and transcriptional-regulation-related proteins, including transcription factors and epigenetic enzymes, and discuss the key influences of the ligands and metal center on bioactivity. Second, we describe transition-metal-based conjugates that indirectly interact with gene regulators. Using the conjugation strategy, effective gene modulators can be developed without requiring extensive screening or compromising the ligand's biological activity. Interestingly, modification of the iridium(III) complex may transform the activity from agonistic to antagonistic, offering new insights into the development of gene regulation modulators. Additionally, these conjugates can serve as effective probes for screening gene regulation modulators with the use of time-resolved measurements to minimize interference from fluorescent molecules.In summary, the studies discussed in this Account describe a series of organometallic iridium(III) and rhodium(III) complexes that specifically bind to gene regulatory proteins. These complexes act through precise three-dimensional binding instead of via redox modulation or covalent interactions. We expect that these complexes could provide the basis for the development of organometallic iridium(III)- and rhodium(III)-based drugs and advance our understanding of activity-based gene regulation.