Identification of CNS-Penetrant Tryptophan 2,3-Dioxygenase Degrading Ligands

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ABSTRACT Tryptophan 2,3-dioxygenase (TDO) is a key modulator of physiological neurogenesis and anxiety-related behavior. Misregulated neuronal TDO activity causes elevated levels of tryptophan-kynurenine pathway metabolites, which in turn, causes depression, brain degeneration, and neurodegenerative Alzheimer's, Parkinson's, and Huntington's diseases. However, a critical need remains for identifying new agents that function through innovative mechanisms to probe a range of pharmacological hypotheses regarding central TDO action, ultimately advancing our overall pharmacological knowledge, and to also serve as leads for downstream medicinal chemistry optimization, thus helping people live long healthy lives. To identify innovative inhibitors, we engaged in a joint basic science-clinical study that identified a non-catalytic L-tryptophan (L-Trp) binding site in human TDO that binds L-Trp surprisingly much tighter than the catalytic heme site. The newly discovered L-Trp binding site is involved in regulating TDO activity and stability by suppressing ubiquitin-dependent degradation when loaded with L-Trp. This finding has inspired us to propose a central hypothesis that this newly discovered signaling site is an Achilles' heel of TDO for drug development. This application will fill the critical need to identify CNS-penetrant protein-degrading ligands for exploring their biomedical potential. Towards this end, we will employ our rigorous understanding of the underlying chemistry and biology to design compounds with a novel mode of action that destabilize the signaling site of TDO or bind without enhancing the protein stability. These agents will not target the catalytic activity of TDO but instead will disrupt its degradation resistance signal. We will assess the effects of promising compounds on human TDO in cellular models to validate the innovative approach and target. In the end, this work will open the door for designing revolutionarily new centrally-active inhibitors targeting human TDO.