A New Mode of Inhibition to Target Protein-Protein Interactions by Ligand-Transferred Oxidation

PROJECT SUMMARY / ABSTRACT The overarching goal of our research group is to establish new ways to inhibit proteins, to unlock targets currently considered undruggable, and to transcend the limitations of current medical interventions. Protein–protein interactions remain challenging targets for conventional small-molecule therapeutics. We recently discovered a new approach to block protein–protein interactions by arming ligands with functional groups that transfer oxygen atoms onto methionine sidechains to block binding interfaces. Ligand-targeted oxidation of a biomedical target protein, exploiting natural and unnatural post-translational oxidative states of sidechains to alter a protein’s function, is unprecedented among known modes of action for therapeutics. We propose the first study to establish the fundamentals of this new strategy, and to harness this long-lived mode of inhibition for blocking challenging protein–protein interactions among key immuno-oncology targets. Our research program covers multiple targets and approaches, on the common theme of sidechain oxidation, deployed to inhibit immune checkpoint protein–protein interactions as the first case-study for this technology. Importantly, our research program aligns with unaddressed medical needs of many cancer patients who cannot benefit from the first-generation antibody-based immune checkpoint inhibitors. Developing ligand-targeted oxygen transfer in this context has the potential to fulfill the long-standing goal of the scientific community to expand immuno-oncology to fight more types of cancer, especially solid tumors and immunologically shielded cancers. More broadly, we envision that precision-targeted oxygen transfer will enable us to inhibit many other challenging biomedical proteins currently deemed undruggable, paving the way to address unmet medical needs that are underserved by conventional small-molecules and antibody-based therapeutics. CONFIDENTIAL—ALBERT EINSTEIN COLLEGE OF MEDICINE JP Maianti, Ph.D. –– Project Summary, Page 1/1