Small Molecule Compounds Inhibiting RAS Effector Interactions
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Solution Overview
Problem
Current therapies for cancer, particularly those targeting mutant RAS proteins, have been ineffective due to the difficulty in specifically inhibiting aberrant RAS function, as most oncogenic proteins are intracellular and not accessible for antibody-mediated targeting, and there is a lack of small-molecule drugs capable of effectively impeding protein-protein interactions.
Innovation Solution
Development of compounds that can penetrate cells and specifically bind to RAS proteins to inhibit RAS-effector protein interactions, utilizing single domain VH intrabodies or small molecules that recognize the conformational structure of oncogenic RAS to disrupt these interactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibody-mediated targeting is used to inhibit RAS proteins, then specificity and affinity can be achieved, but most oncogenic proteins including RAS are located inside cells and not accessible for antibody-mediated targeting
Solution Approach 1:
The patent uses intracellular delivery systems as intermediaries to transport antibodies into cells. The antibody is not administered directly to the intracellular target but is carried by a delivery vehicle that penetrates the cell membrane, thus mediating the interaction between the antibody and the intracellular RAS protein.
Solution Approach 2:
The patent employs a nested structure where the antibody is contained within an intracellular delivery system. The delivery system (such as a viral vector or liposome) is nested inside the cell, and the antibody is nested within the delivery system, allowing sequential delivery through multiple barriers to reach the intracellular target.
2Ease of operation
If small molecule drugs are used to impede protein-protein interactions, then cell penetration is achieved, but there is a lack of small-molecule drugs capable of effectively impeding protein-protein interactions
Solution Approach 1:
The patent modifies the chemical parameters of small molecules to enhance their ability to bind to protein-protein interaction interfaces. By changing molecular size, shape, charge distribution, and functional groups, the small molecules are optimized to achieve both cell penetration and effective disruption of protein-protein interactions.
3Reliability
If Farnesyltransferase inhibitors are used to block RAS signaling, then membrane localisation of RAS proteins can be inhibited, but the antitumour activity may only partly be due to targeting RAS and may also affect farnesylation of other proteins
Solution Approach 1:
The patent develops inhibitors that are highly specific to the RAS-farnesyltransferase interaction site. By designing molecules that target only the specific binding interface between RAS and farnesyltransferase, with precise spatial and chemical complementarity, the inhibitor achieves selective inhibition without affecting other farnesylation substrates.
Data Source
AI summary
The present invention relates to compounds of Formula I as defined herein, and salts and solvates thereof. (I) The present invention also relates to pharmaceutical compositions comprising compounds of Formula (I), and to compounds of Formula (I) for use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which inhibition of a RAS-effector protein-protein interaction is implicated.