Targeting Nascent MYC Translation via Ribosome Complex Inhibition
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current approaches lack effective methods to target c-MYC and n-MYC proteins with small molecule inhibitors due to their lack of defined ligand binding sites and intrinsically disordered structure, limiting therapeutic options for cancers driven by these proteins.
Innovation Solution
Development of compounds that inhibit c-MYC or n-MYC translation by targeting the cytosolic nascent chain/ribosome complex, allowing for partial inhibition and minimizing impact on normal tissues, using substituted amides that engage the ribosome nascent chain to modulate MYC activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule inhibitors are used to target c-MYC or n-MYC proteins, then therapeutic treatment of cancer is achieved, but the lack of defined ligand binding sites and intrinsically disordered structure prevents effective drug binding
Solution Approach 1:
The patent applies preliminary action by targeting the nascent c-MYC/n-MYC protein chain during its synthesis process on the ribosome, before the protein folds into its final intrinsically disordered structure. This allows small molecule compounds to bind to the nascent chain-ribosome complex at an early stage, circumventing the ligand binding site problem of the mature protein.
Solution Approach 2:
The patent uses the ribosome as an intermediary target. Instead of directly targeting the difficult-to-bind c-MYC/n-MYC protein, the small molecule compounds bind to the ribosome-nascent chain complex. The ribosome serves as a mediator that presents the nascent protein chain in a druggable format, enabling effective inhibition without requiring direct binding to the disordered protein structure.
2Productivity
If full inhibition of c-MYC or n-MYC is achieved, then tumor regression is maximized, but impact on normal tissues increases
Solution Approach 1:
The patent applies partial action by achieving sufficient tumor regression through inhibition of c-MYC/n-MYC translation without requiring complete blockade. The compounds stall translation at a level that promotes proliferative arrest and apoptosis in cancer cells while allowing enough translation to occur to minimize impact on normal tissues, thereby optimizing the therapeutic index.
Solution Approach 2:
The patent exploits local quality differences between cancer cells and normal cells. Cancer cells with dysregulated c-MYC/n-MYC expression are more sensitive to translation stalling at partial inhibition levels, while normal cells with regulated expression tolerate the same level of inhibition better. This differential sensitivity allows selective anti-tumor activity with reduced toxicity to normal tissues.
3Reliability
If translation stalling compounds are used to target nascent chain/ribosome complex, then therapeutic index is improved, but currently no effective approaches exist to target c-MYC or n-MYC with small molecules
Solution Approach 1:
The patent applies parameter changes by identifying specific structural features and substitution patterns in substituted amide compounds that optimize their ability to stall translation of c-MYC/n-MYC. By systematically varying chemical parameters (substituents on the aromatic ring, amide group modifications, stereochemistry), the patent discovers compounds with improved potency and selectivity for the ribosome-nascent chain complex.
Data Source
AI summary
A method of modulating c-MYC activity is disclosed. The method includes administering an effective amount of a compound of Formula I