Cyclopropylamine LSD1 Inhibitor Combinations for Reduced MAO-A Inhibition
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Solution Overview
Problem
Current LSD1 inhibitors, such as Tranylcypromine, exhibit undesired side effects due to MAO-A inhibition, necessitating the development of cyclopropylamine derivatives with potent LSD1 inhibitory activity while minimizing MAO-A inhibitory activity.
Innovation Solution
A therapeutic combination of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine or its pharmaceutically acceptable salts with active pharmaceutical ingredients like BCL2 inhibitors, BET inhibitors, EZH2 inhibitors, DNA alkylating agents, and others, to synergistically inhibit cancer cell growth.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Tranylcypromine is used as an LSD1 inhibitor, then LSD1 inhibitory activity is achieved, but MAO-A inhibition occurs causing undesired side effects
Solution Approach 1:
The patent extracts the desired LSD1 inhibitory function from the cyclopropylamine structure while removing the harmful MAO-A inhibition property. This is achieved by modifying the cyclopropylamine structure to create selective LSD1 inhibitors that do not inhibit MAO-A, thereby separating the beneficial effect from the harmful side effect.
Solution Approach 2:
The patent applies local quality by introducing specific structural modifications at particular positions of the cyclopropylamine molecule. These localized changes (such as substituent patterns and stereochemistry) enhance LSD1 selectivity while maintaining or reducing MAO-A activity, allowing different parts of the molecule to have different functional properties.
2Reliability
If combination therapy with multiple active pharmaceutical ingredients is used, then synergistic anti-cancer effect is enhanced, but treatment complexity increases
Solution Approach 1:
The patent combines multiple active pharmaceutical ingredients with different mechanisms of action into a single therapeutic regimen. The LSD1 inhibitor is administered in combination with other anti-cancer agents to achieve synergistic effects, where the combined therapy produces greater anti-cancer efficacy than the sum of individual treatments.
Solution Approach 2:
The patent creates a multi-functional treatment approach where the LSD1 inhibitor works through multiple mechanisms: directly inhibiting LSD1 enzyme activity, modulating gene expression patterns, and enhancing the efficacy of concomitant anti-cancer therapies. This multi-functionality allows a single agent to address multiple aspects of cancer pathophysiology.
Data Source
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AI summary
The instant invention relates to therapeutic combinations of LSD1 inhibitors and one or more other active pharmaceutical ingredient(s) or pharmaceutically acceptable salts thereof. The combinations are particularly useful for treating neoplastic diseases, such as cancer, particularly small cell lung cancer (SCLC).