Splice Modulating Compounds for Cancer Treatment

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Solution Overview

Problem

Current splicing modulators, such as FD-895, pladienolides, and herboxadiene, face limitations in enhanced biological activity and stability, which hinders their effectiveness in treating cancers like leukemia and lymphoma.

Innovation Solution

Development of new compounds with specific structures, such as those described by Formula (I), which modulate splicing and inhibit the spliceosome, offering improved pharmacological properties compared to existing analogs, including pharmaceutical compositions and methods for treating cancer and detecting splicesome inhibition.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current splicing modulators (FD-895, pladienolides, herboxadiene) are used, then splicing modulation activity is achieved, but biological stability and activity are insufficient

Engineering Contradiction:

Improvebiological stabilityVSAvoidmolecular structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by systematically modifying molecular parameters of splicing modulators, including substituting hydroxy groups with methoxy groups, altering ring structures, and changing side chain configurations. These parameter modifications enhance metabolic stability and biological activity while maintaining the core splicing modulation function, directly resolving the contradiction between stability and structural complexity.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite material principles by creating hybrid molecular structures that combine stable structural cores with functional side chains. The compounds integrate rigid polycyclic cores providing stability with flexible substituent groups maintaining biological activity, effectively resolving the contradiction between structural stability and functional complexity.

Inventive Principle:

Principle #40Composite materials

2Reliability

If natural product-based splice modulators are used, then splicing inhibition is achieved, but pharmacological properties are limited

Engineering Contradiction:

Improvepharmacological activityVSAvoidsynthetic accessibility

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies segmentation by dividing complex natural product structures into modular synthetic components. The molecules are constructed from discrete building blocks including polycyclic cores, linker regions, and functional end-groups, enabling systematic optimization of pharmacological properties while simplifying manufacturing through modular assembly of well-defined fragments.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent inverts the traditional approach by starting with simplified synthetic cores and building up complexity through controlled addition of functional groups, rather than attempting to synthesize complete natural products. This reverse strategy achieves comparable or superior pharmacological activity with significantly improved synthetic accessibility.

Inventive Principle:

Principle #13The other way round (Inversion)

Data Source

PatentUS11203588B2Anti-cancer and splice modulating compounds and methods

Publication Date: 2021.12.21 RGT UNIV OF CALIFORNIA

AI summary

There are provided inter alia stable anti-cancer compounds and splice modulators and methods of synthesis and use thereof.