Crosslinked Chiral Secondary Amine for Menin-MLL Inhibition

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Solution Overview

Problem

Existing small molecular inhibitors fail to effectively inhibit the binding between MLL fusion proteins and menin, which are implicated in various cancers, without causing safety issues related to hERG current inhibition.

Innovation Solution

A crosslinked optically active secondary amine derivative, represented by formula (1), is developed to potently inhibit the binding between menin and MLL fusion proteins, offering a therapeutic window between cell proliferation inhibition and hERG current inhibition.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing small molecular inhibitors are used to inhibit the binding between MLL fusion proteins and menin, then antitumor effect is achieved, but safety issues arise due to hERG current inhibition

Engineering Contradiction:

Improveantitumor effectVSAvoidhERG current inhibition

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the chemical structure of existing inhibitors by changing molecular parameters - specifically introducing a crosslinked optically active secondary amine derivative with specific stereochemistry and functional groups. This structural parameter change allows the compound to maintain binding affinity to MLL-menin while altering its interaction with hERG channels, thereby achieving antitumor efficacy without the harmful cardiac side effects

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite molecular structure combining multiple functional elements: the optically active secondary amine core, crosslinking groups, and specific substituent patterns. This composite structure enables selective binding to MLL-menin while the spatial arrangement of functional groups prevents hERG channel interaction, resolving the safety issue

Inventive Principle:

Principle #40Composite materials

2Productivity

If compound concentration is increased to enhance antitumor effect, then cell proliferation inhibition improves, but hERG current inhibition becomes more severe

Engineering Contradiction:

Improvecell proliferation inhibitionVSAvoidhERG current inhibition

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the pharmacological parameters of the compound through structural modification - specifically using crosslinked optically active secondary amine derivatives with optimized binding affinity. This allows achieving effective cell proliferation inhibition at lower concentrations, thereby avoiding the concentration-dependent hERG current inhibition that plagues existing inhibitors

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS12559487B2Crosslinked optically active secondary amine derivative

Publication Date: 2026.02.24 SUMITOMO PHARMA CO LTD

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, Ring A is cycloalkylene or the like, L is single bond or the like, and R is methyl or the like, or a pharmaceutically acceptable salt thereof, which has an anticancer effect by inhibiting the binding between a MLL fusion protein that is fused with AF4, AF9, or the like, which is a representative fusion partner gene causing MLL leukemia, and menin.