GSPT1 Modulators for Premature Termination Codon Readthrough
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for genetic disorders caused by nonsense mutations, such as cystic fibrosis and muscular dystrophy, face limitations due to systemic toxicity and inadequate readthrough activity of premature termination codons, necessitating the development of compounds with enhanced readthrough activity and reduced toxicity.
Innovation Solution
The use of GSPT1 modulators, specifically compounds of formula I or their pharmaceutically acceptable salts, either alone or in combination with aminoglycosides, to promote readthrough of premature termination codons, thereby restoring full-length protein synthesis and treating associated diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If aminoglycosides are used to induce readthrough of premature termination codons, then functional protein production is restored, but systemic toxicity increases
Solution Approach 1:
The patent modifies the chemical structure of aminoglycosides by replacing the amino sugar moiety with heterocyclic rings (pyrimidine, triazole, tetrazole, oxadiazole, or thiadiazole) to create analogs with altered pharmacological properties. This structural parameter change maintains or enhances readthrough activity while reducing systemic toxicity compared to conventional aminoglycosides
Solution Approach 2:
The invention creates composite molecular structures by combining the core aminoglycoside scaffold with heterocyclic moieties. These hybrid compounds integrate the beneficial readthrough-inducing properties of aminoglycosides with the favorable pharmacological characteristics of heterocyclic compounds, achieving both efficacy and safety
2Quantity of substance
If conventional aminoglycosides are administered to treat nonsense mutation-mediated genetic disorders, then some functional protein production is achieved, but therapeutic benefits are limited due to toxicity
Solution Approach 1:
The patent systematically varies chemical parameters including the type of heterocyclic ring (pyrimidine, triazole, tetrazole, oxadiazole, thiadiazole), substitution patterns, and linker structures to optimize the balance between protein production efficacy and therapeutic safety profile
Data Source
AI summary
The present disclosure relates to a compound of formula I or a pharmaceutically acceptable salt thereofwherein A isX1 is linear or branched C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X1 is unsubstituted or substituted with one or more of halogen, linear or branched C1-6 alkyl, linear or branched C1-6 heteroalkyl, CF3, CHF2, CMeF2, —O—CHF2, —O—(CH2)2—OMe, OCF3, C1-6 alkylamino, —CN, —N(H)C(O)—C1-6alkyl, —OC(O)—C1-6alkyl, —OC(O)—C1-4alkylamino, —C(O)O—C1-6alkyl, —COOH, —CHO, —C1-6alkylC(O)OH, —C1-6alkylC(O)O—C1-6alkyl, NH2, C1-6 alkoxy or C1-6 alkylhydroxy; or X1 together with X4 forms a 4-8 membered heterocycloalkyl, which is unsubstituted or substituted with one or more of halogen, linear or branched —C1-6 alkyl, CF3, CHF2, CMeF2, —O—(CH2)2—OMe, OCF3, OCHF2, C1-6 alkylamino, —CN, —N(H)C(O)—C1-6alkyl, —OC(O)—C1-6alkyl, —C(O)O—C1-6alkyl, —COOH, —C1-6alkylC(O)OH, —C1-6alkylC(O)O—C1-6alkyl, NH2, C1-4 alkylhydroxy, or C1-6 alkoxy; X2 is hydrogen, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2 is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, —C1-4 alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, —O—(CH2)2—OMe, OCF3, OCHF2, C1-4 alkylhydroxy; X3 is —NH—, —O—; X4 is —NH—, —CH2—; L1 is a covalent bond, C1-6 alkyl, which is unsubstituted or substituted with one or more of C1-4 alkyl, halogen; L2 is a covalent bond, C1-6 alkyl, which is unsubstituted or substituted with one or more of C1-4 alkyl, halogen; L3 is a covalent bond, —O—, —C1-4 alkoxy or C1-6 alkyl, which is unsubstituted or substituted with one or more of C1-4 alkyl, halogen, for use in the prevention and treatment of a disease or disorder caused by or associated with one or more premature termination codons in a monotherapy or in a combined therapy with an aminoglycoside or a pharmaceutically acceptable salt thereof.