Mutant IDH Inhibitor Solid Forms for Cancer Treatment
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Solution Overview
Problem
Mutations in IDH1 and IDH2 enzymes in cancer cells lead to the production of R(−)-2-hydroxyglutarate (2HG), contributing to cancer formation and progression, and existing treatments lack effective inhibitors for these mutated enzymes.
Innovation Solution
Development of solid forms, such as salts, cocrystals, and amorphous solid dispersions, of a compound that acts as an inhibitor of mutant IDH1 and IDH2 proteins, specifically 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, to treat cancers characterized by these mutations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments are used for mutant IDH1 and IDH2, then general cancer treatment protocols are applied, but they fail to effectively inhibit the mutated enzymes and halt 2HG production
Solution Approach 1:
The patent modifies the chemical structure parameters of the compound by creating different solid forms (salts, cocrystals, amorphous solid dispersions) to optimize the pharmacological properties. Specifically, the compound of formula (I) and its solid forms are designed to achieve optimal binding affinity to mutant IDH enzymes while maintaining selective inhibition, thereby improving treatment effectiveness and enzyme specificity simultaneously
Solution Approach 2:
The invention creates highly specific local interactions between the compound and the mutant IDH enzyme active site. The molecular structure is designed to fit specifically into the mutated enzyme's binding pocket, creating localized high-affinity binding that distinguishes mutant from wild-type enzymes, thus achieving both effectiveness and specificity
2Stability of the object's composition
If solid forms of the compound are developed, then bioavailability and stability are improved, but the complexity of formulation and characterization increases
Solution Approach 1:
The patent segments the compound into different solid forms (salts, cocrystals, amorphous solid dispersions) to optimize stability and bioavailability. Each solid form is characterized by specific properties, allowing selection of the most appropriate form for the intended application, thereby managing complexity through systematic classification
Solution Approach 2:
The invention creates composite solid forms by combining the active compound with various counterions, coformers, or excipients in defined ratios. These composite materials (salts and cocrystals) exhibit enhanced stability and solubility properties compared to the pure compound, while the systematic approach to formulation reduces overall complexity
Data Source
AI summary
Provided are solid forms of a compound useful for treating cancer, such as pharmaceutically acceptable salts and cocrystals, pharmaceutical compositions thereof, and use for the treatment cancer comprising administering the solid forms described herein to a patient in need thereof.