Small Molecule Splicing Modulators for Oral pre-mRNA Control
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Solution Overview
Problem
Current therapeutic approaches for modulating mRNA expression, such as gene therapy and oligonucleotide therapies, face challenges including unfavorable pharmacokinetics, lack of oral bioavailability, poor blood-brain-barrier penetration, and inefficiency in accessing cellular compartments, particularly in treating neurological diseases and solid tumors.
Innovation Solution
Development of small molecule splicing modulators (SMSMs) that can modulate splicing processes without the structural and steric hindrances of oligonucleotides, offering a novel therapeutic approach to target RNA-mediated diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oligonucleotide therapies are used to modulate mRNA expression, then splicing can be controlled, but pharmacokinetics are unfavorable and oral bioavailability is lacking
Solution Approach 1:
The patent replaces oligonucleotide-based mechanisms (which rely on canonical base pairing and have poor pharmacokinetics) with small molecule mechanisms that interact with pre-mRNA through non-canonical binding modes. This substitution enables oral bioavailability while maintaining splicing control capability, as small molecules can cross the blood-brain barrier and be absorbed orally unlike oligonucleotides.
2Reliability
If oligonucleotide therapies are used to target pre-mRNA, then splicing can be modulated, but structural and steric hindrances from pre-mRNA complexity limit effectiveness
Solution Approach 1:
The patent changes the binding parameters from canonical base pairing (oligonucleotide approach) to alternative interaction modes suitable for small molecules. This allows the therapeutic agent to bind to pre-mRNA despite its complex secondary and tertiary structures, cis-acting elements, and trans-acting factors that hinder oligonucleotide access.
3Quantity of substance
If oligonucleotides are administered parenterally, then they can reach systemic circulation, but they cannot penetrate the blood-brain barrier to treat neurological diseases
Solution Approach 1:
The patent substitutes oligonucleotide delivery systems with small molecule compounds that inherently possess blood-brain barrier penetration capability. This allows treatment of neurological diseases through oral administration, combining systemic circulation delivery with CNS access that oligonucleotides cannot achieve.
4Reliability
If oligonucleotides are used for gene therapy or genome editing, then mRNA expression can be controlled upstream, but technical and regulatory challenges arise
Solution Approach 1:
The patent replaces complex gene therapy and genome editing approaches with small molecule splicing modulators that act at the pre-mRNA level. This substitution simplifies the technical and regulatory landscape while maintaining the ability to control mRNA expression, avoiding the substantial challenges associated with DNA-level interventions.
Data Source
AI summary
Described herein are small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, pharmaceutical compositions comprising the same, and methods of the small molecule splicing modulator compounds for modulating splicing and treating disease and conditions. In one aspect, disclosed herein are small molecule splicing modulators having a structure of Formula (II), or pharmaceutically acceptable salts thereof.