Optically Active Azabicyclo Ring Derivative for Menin-MLL Inhibition
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Solution Overview
Problem
Current treatments for MLL leukemia and related cancers lack effective inhibitors that specifically target the binding between MLL fusion proteins and menin, leading to inadequate therapeutic outcomes with potential safety concerns due to narrow therapeutic windows.
Innovation Solution
Development of an optically active azabicyclo ring derivative or its pharmaceutically acceptable salt, which exhibits a potent inhibitory effect on the binding between menin and MLL fusion proteins, offering a broader safety margin and enhanced therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for MLL leukemia are used, then therapeutic effect is limited, but safety concerns arise due to narrow therapeutic windows
Solution Approach 1:
The patent applies parameter changes by developing a series of optically active azabicyclo ring derivatives with specific structural parameters (formula 1) that achieve superior binding affinity to the menin-MLL interface. The compound of formula (1) and its pharmaceutically acceptable salts represent a parameter optimization in molecular structure to enhance therapeutic effect while improving safety profile through broader therapeutic window
Solution Approach 2:
The patent employs an intermediary approach by designing a small molecular inhibitor that specifically targets and blocks the binding interface between menin and MLL fusion protein. The compound of formula (1) acts as a molecular intermediary that interferes with the pathological interaction, preventing MLL fusion protein from binding to menin and thereby inhibiting unrestrained proliferation of hematopoietic cells
2Productivity
If small molecular inhibitors targeting menin-MLL binding are developed, then therapeutic efficacy improves, but compound specificity and safety margin must be enhanced
Solution Approach 1:
The patent applies local quality by designing the optically active azabicyclo ring derivative with specific local structural features (substituents R1-R4, p value of 1 or 2, and chiral centers) that target the specific binding pocket of the menin-MLL interface. This localized molecular design ensures high specificity for the menin-MLL binding site while maintaining therapeutic efficacy
Solution Approach 2:
The patent employs asymmetry through the use of optically active (chiral) azabicyclo ring structures. The compound of formula (1) contains chiral centers that create asymmetric molecular geometry, which is critical for achieving high specificity and affinity for the chiral binding interface of menin-MLL. This asymmetric structure distinguishes the compound from achiral analogs and enhances both efficacy and safety margin
Data Source
AI summary
The present invention relates to the compound of formula (1a) wherein p is 1 or 2, R1-R4 are hydrogen atom or the like, and a-d are 1 or 2, or a pharmaceutically acceptable salt thereof, which has an antitumor effect by inhibiting the binding between a MLL fusion protein that is infused with AF4, AF9, or the like, which is a representative fusion partner gene causing MLL leukemia, and menin.