TDO IDO Inhibitors Block Tryptophan Catabolism
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Solution Overview
Problem
Current treatments for various diseases, including cancer, inflammatory conditions, and infectious diseases, are limited by the immunosuppressive effects of tryptophan catabolism mediated by tryptophan-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO), which suppress immune responses and promote tumor growth and immunopathology.
Innovation Solution
Development of TDO and IDO inhibitors that prevent the conversion of tryptophan into N-formylkynurenine, thereby modulating tryptophan metabolism to enhance immune responses and inhibit tumor growth and immunosuppression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If tryptophan catabolism is allowed to proceed through TDO and IDO enzymes, then immunosuppression is reduced and immune responses are enhanced, but tumor growth is promoted and immunopathology occurs
Solution Approach 1:
The patent uses small molecule inhibitors as intermediaries to block the enzymatic activity of TDO and IDO. These inhibitors bind to the active sites of the enzymes, preventing tryptophan conversion to kynurenine without directly interacting with the immune system or tumor cells themselves, thus mediating the effect between tryptophan metabolism and immune-tumor balance
Solution Approach 2:
The patent changes the metabolic parameter by blocking the conversion of tryptophan to kynurenine through TDO/IDO inhibition. This parameter change (maintaining tryptophan levels, reducing kynurenine levels) subsequently affects immune function and tumor growth without requiring direct modification of immune cells or tumor biology
2Reliability
If TDO and IDO inhibitors are used to enhance immune responses, then immune function is restored and tumor growth is inhibited, but the complexity of treatment regimens increases
Solution Approach 1:
The patent develops inhibitors with dual activity against both TDO and IDO enzymes, allowing a single compound to address multiple enzymatic pathways involved in tryptophan catabolism. This multi-functionality reduces treatment complexity compared to using separate inhibitors for each enzyme
Solution Approach 2:
The patent employs combination therapy where TDO/IDO inhibitors are administered alongside other immunotherapies or chemotherapy agents. The inhibitors prepare the tumor microenvironment by reducing immunosuppression and enhancing immune cell function beforehand, making subsequent therapies more effective and potentially reducing the need for higher doses of other treatments
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The inhibitors effectively restore immune function, reduce tumor growth, and improve outcomes in cancer, inflammatory, and infectious diseases by lowering kynurenine levels and relieving immunosuppression, allowing for enhanced immune attack on tumors and pathogens.
Implementation Method 1
Both enzymes catalyze the oxidative cleavage of the 2,3 double bond in the indole ring, converting tryptophan to N-formylkynurenine
Data Source
AI summary
Provided is a tryptophan-2,3-dioxygenase (TDO) and/or indoleamine-2,3-dioxygenase (IDO) inhibitor compound for use in medicine, which compound comprises the following formula: wherein X1, X2, X3, X4, and X5 may be the same or different and each is independently selected from C, N and O; each atom having a dotted line may independently have a double bond or a single bond, provided that valencies at each atom are maintained; each R1, R2, R3, R4, and R7 may be present or absent and may be the same or different and is selected from H and a substituted or unsubstituted organic group, provided that the number of such R groups present is such that the valencies of X1, X2, X3, X4, and X5 are maintained; one or two R6 groups may be present and are selected from H and a substituted or unsubstituted organic group, provided that the number of R6 groups present is such that the valency of the carbon atom to which they are attached is maintained, and provided that at least one R6 is an organic group comprising an atom double-bonded to an oxygen atom (preferably a carbonyl group or a sulphonyl group) at an α-, β-, or γ-position to the carbon atom to which the R6 is attached and in which the atom double-bonded to an oxygen atom is also bonded to a hetero-atom.