Selective MTHFD1 and MTHFD2 Inhibitors for One-Carbon Metabolism
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Solution Overview
Problem
Current treatments for proliferative diseases such as cancer and autoimmune disorders, which target the one-carbon metabolism pathway, often come with significant side effects due to non-specific inhibition of enzymes like dihydrofolate reductase.
Innovation Solution
Development of compounds that selectively inhibit cytoplasmic and mitochondrial enzymes involved in the one-carbon metabolism pathway, specifically targeting MTHFD1 and MTHFD2, to reduce side effects and enhance therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If compounds like MTX and 5-FU are used to target one-carbon metabolism pathway, then excessive cell proliferation is suppressed, but numerous side effects occur due to non-specific inhibition
Solution Approach 1:
The invention segments the one-carbon metabolism pathway into distinct cellular compartments (cytoplasmic MTHFD1 and mitochondrial MTHFD2) and develops compounds that can selectively target specific isoforms. This segmentation allows differential inhibition of enzyme isoforms responsible for pathogenic cell proliferation while sparing enzymes in normal cells, thereby reducing side effects while maintaining therapeutic efficacy.
Solution Approach 2:
The patent applies local quality by designing compounds with specific molecular characteristics that enable selective binding to MTHFD2 in proliferating cells. The compounds exhibit localized action primarily in rapidly dividing cells where MTHFD2 is overexpressed, while having minimal impact on normal cells with lower MTHFD2 expression, thus achieving targeted therapy with reduced systemic toxicity.
2Reliability
If selective inhibition of MTHFD2 is implemented, then therapeutic efficacy is enhanced with reduced side effects, but compound specificity and selectivity must be precisely controlled
Solution Approach 1:
The invention employs parameter changes by systematically modifying molecular parameters of the compounds (such as substituent groups on the core structure) to optimize selectivity for MTHFD2 over MTHFD1. By adjusting these chemical parameters, the compounds achieve enhanced binding affinity and specificity for the target enzyme isoform, ensuring reliable therapeutic efficacy while minimizing off-target effects.
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 selective inhibition of MTHFD2 and MTHFD1 enzymes in the one-carbon metabolism pathway effectively reduces excessive cell proliferation associated with diseases like cancer and autoimmune disorders, while minimizing side effects compared to existing treatments.
Implementation Method 1
MTHFD2 dehydrogenase/cyclohydrolase domain (D/C-d) first converts 5,10 me-tetrahydrofolate to 10-formyl tetrahydrofolate via oxidation mediated by NAD
Implementation Method 2
MTHFD1 dehydrogenase/cyclohydrolase domain (D/C-d) first converts 5,10 me-tetrahydrofolate to 10-formyl tetrahydrofolate via oxidation mediated by NADP
Data Source
AI summary
The invention relates to compounds of formula (I)and related aspects.