KDM5 Inhibitor Compounds Selective Binding
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Solution Overview
Problem
Current therapies lack effective modulators for histone demethylases like KDM5A, which are overexpressed in various cancers, leading to poor prognosis and drug resistance, necessitating the development of selective inhibitors for therapeutic intervention.
Innovation Solution
Development of compounds of Formulae (I) and (II) and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs that selectively inhibit KDM5 histone demethylase activity, potentially treating proliferative diseases such as cancer and cardiovascular diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used, then treatment of proliferative diseases continues, but effective modulation of histone demethylases like KDM5A is lacking, leading to poor prognosis and drug resistance
Solution Approach 1:
The patent applies parameter changes by developing compounds with specific molecular structures (Formulae I and II) that target the unique active site architecture of KDM5A. The compounds feature specific substituent patterns (R1, R2, R3, Ring A, Ring B) and structural parameters (n, z) that are optimized to match the binding pocket characteristics of KDM5A, enabling selective inhibition while maintaining therapeutic efficacy against proliferative diseases
2Reliability
If selective KDM5 inhibitors are developed, then therapeutic intervention for cancer and cardiovascular diseases is improved, but the complexity of compound structure and synthesis increases
Solution Approach 1:
The patent applies segmentation by dividing the inhibitor molecule into distinct functional modules: a core structure (Formula I or II) with specific substituent positions (R1, R2, R3) and two ring systems (Ring A and Ring B). This modular design allows for systematic optimization of each segment's contribution to binding affinity and selectivity, managing molecular complexity through structured organization of functional elements
Solution Approach 2:
The patent applies universality by designing a core structural framework (Formulae I and II) that can accommodate multiple substituent variations while maintaining the essential KDM5A binding interactions. The general formula structure serves as a universal scaffold that can be adapted to generate multiple specific inhibitors with different pharmacokinetic properties, enabling broad therapeutic application across various proliferative diseases
Data Source
AI summary
Provided herein are compounds of Formulae (I) and (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the compounds or compositions disclosed herein for treating and/or preventing proliferative diseases, cancers, carcinoma lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, ovarian cancer, colon cancer, colorectal cancer, leukemia, sarcoma and/or cardiovascular diseases in a subject in need thereof. In certain embodiments, the sarcoma is Ewing's sarcoma. Provided are methods of inhibiting a histone demethylase in a subject and/or in a cell, tissue, or biological sample. In certain embodiments, the histone demethylase is a KDM. In certain embodiments, the KDM is KDM5. In certain embodiments the biological sample is a cell. In certain embodiments, the biological sample is a tissue.