Small Molecule Splicing Modulators for RNA Targeting
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Solution Overview
Problem
Current therapeutic approaches for controlling mRNA expression, such as gene therapy and oligonucleotide technologies, face challenges including unfavorable pharmacokinetics, lack of oral bioavailability, and difficulty penetrating the blood-brain barrier, as well as structural and steric hindrances due to the complex secondary and tertiary structure of pre-mRNA, limiting their effectiveness in treating RNA-mediated diseases.
Innovation Solution
Development of small molecule splicing modulators (SMSMs) that interact with unpaired bulged nucleobases in RNA duplexes at splice sites, modulating splicing processes without the limitations faced by oligonucleotides, and are designed to be specific, potent, and orally available.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If oligonucleotide therapies are used to modulate mRNA expression, then specific binding to target sequences can be achieved, but unfavorable pharmacokinetics and lack of oral bioavailability occur
Solution Approach 1:
The patent changes the chemical parameters of the therapeutic agent by using small molecule compounds with specific chemical structures (Formula I and Formula II) that have improved pharmacokinetic properties including oral bioavailability, while maintaining the ability to bind to and modulate pre-mRNA splicing through molecular interactions with RNA structures
2Measurement precision
If oligonucleotide therapies are used to target pre-mRNA, then splicing modulation can be achieved, but blood-brain barrier penetration is prevented
Solution Approach 1:
The patent changes the physicochemical parameters of the therapeutic agent by employing small molecule compounds with appropriate molecular weight, lipophilicity, and structural characteristics that enable penetration through the blood-brain barrier, while maintaining specific interaction with pre-mRNA splice sites through molecular recognition
3Measurement precision
If oligonucleotide therapies are used to anneal to target sequences, then base pairing can be achieved, but structural and steric hindrances from pre-mRNA complexity limit effectiveness
Solution Approach 1:
The patent replaces the mechanical base-pairing mechanism of oligonucleotides with a small molecule binding mechanism that recognizes and binds to specific structural motifs in pre-mRNA, such as bulged nucleobases and RNA duplexes, thereby overcoming the limitations imposed by pre-mRNA secondary and tertiary structures
4Measurement precision
If oligonucleotide therapies are used for splicing modulation, then mRNA expression control can be achieved, but delivery to solid tumors requires complex delivery systems
Solution Approach 1:
The patent changes the delivery-related parameters by using small molecule compounds with improved cellular uptake properties and tissue penetration capabilities, eliminating the need for complex delivery systems such as lipid nanoparticles while maintaining effective delivery to solid tumors and other target tissues
Data Source
AI summary
Described herein are small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, and methods of use of the small molecule splicing modulator compounds for modulating splicing and treating diseases and conditions.