IDH Inhibitor Composition for Blocking D-2-HG Formation
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Solution Overview
Problem
Existing treatments fail to effectively inhibit the conversion of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which is catalyzed by mutated isocitrate dehydrogenase (IDH) enzymes, leading to hypermethylation and aberrant gene expression associated with various cancers.
Innovation Solution
Development of a compound, represented by Formula (Ie) or its pharmaceutically acceptable salts, that inhibits the conversion of α-KG to D-2-HG, targeting both mutant and wild-type IDH enzymes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments are used, then treatment is provided, but the conversion of α-KG to 2-HG is not effectively inhibited
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of IDH inhibitors to achieve optimal binding affinity and selectivity. The compound of Formula (Ie) incorporates specific structural features (R1-R6 substituents) that optimize the interaction with mutant IDH enzymes, thereby effectively inhibiting the conversion of α-KG to D-2-HG while minimizing harmful effects.
Solution Approach 2:
The patent converts the harmful effect of D-2-HG accumulation into a beneficial therapeutic outcome by designing inhibitors that specifically target mutant IDH enzymes. The compound exploits the neomorphic activity of mutant IDH (which produces harmful D-2-HG) and converts this into a therapeutic opportunity by blocking the enzyme's ability to generate D-2-HG, thereby treating cancer-associated conditions.
2Object-generated harmful factors
If IDH mutations are present, then cancer development is promoted, but the enzyme conversion activity is altered
Solution Approach 1:
The patent applies local quality by designing inhibitors with specific structural features that target particular regions of the IDH enzyme active site. The compound of Formula (Ie) incorporates substituents (R1-R6) that are specifically positioned to interact with mutant residues (such as R132H in IDH1), thereby selectively inhibiting the altered enzymatic function while preserving normal IDH activity in wild-type enzymes.
Solution Approach 2:
The patent inverts the approach by instead of trying to restore normal enzyme function, it directly blocks the harmful neomorphic activity of mutant IDH. The inhibitor binds to the mutant enzyme's active site and prevents the conversion of α-KG to D-2-HG, thereby reversing the harmful effect without needing to restore the original enzymatic function.
3Object-generated harmful factors
If D-2-HG accumulates, then hypermethylation occurs, but gene expression is disrupted
Solution Approach 1:
The patent applies preliminary action by preventing D-2-HG accumulation before it can cause hypermethylation and disrupt gene expression. The inhibitor of Formula (Ie) blocks the IDH enzyme's conversion of α-KG to D-2-HG at an early stage, thereby preventing the downstream harmful effects including DNA hypermethylation and aberrant gene expression without needing to reverse already-established epigenetic changes.
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 compound effectively reduces D-2-HG accumulation, thereby modulating gene expression and potentially treating diseases associated with IDH mutations, including brain tumors and leukemia.
Implementation Method 1
Isocitrate dehydrogenase (IDH) is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle which catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate, α-KG) and CO2
Data Source
Figure 1
AI summary
Disclosed are compounds inhibiting the conversion of α–KG to D-2-HG, pharmaceutically acceptable salts, hydrates, solvates or stereoisomers thereof and pharmaceutical compositions comprising the compounds. The compound and the pharmaceutical composition can effectively treat IDH associated diseases, including cancer.