Thienopyrimidine Small Molecules Targeting Ras GTP Binding
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Solution Overview
Problem
Current treatments for cancer, inflammatory diseases, and fibrotic diseases, particularly those related to aberrant Ras signaling, face challenges due to the 'undruggable' nature of the Ras GTP binding domain, leading to resistance and limited therapeutic options.
Innovation Solution
Development of small molecules that competitively bind to the GTP binding domain of Ras, Rac, and Rho proteins, inhibiting GTP binding and disrupting aberrant signaling pathways, thereby inhibiting the activation of ERK1/2 and AKT pathways and reducing cellular proliferation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for cancer and inflammatory diseases, then existing therapeutic options are maintained, but treatment resistance develops and therapeutic effectiveness is limited due to the undruggable nature of the Ras GTP binding domain
Solution Approach 1:
The patent changes the chemical and structural parameters of therapeutic compounds by developing novel small molecule structures (compounds of Formula I and their salts) that can bind to the Ras GTP binding domain. This parameter change enables the previously 'undruggable' target to be effectively targeted, overcoming treatment resistance and improving therapeutic effectiveness in cancers and inflammatory diseases
Solution Approach 2:
The patent introduces small molecule compounds as intermediary substances that mediate the inhibition of Ras protein function. These compounds act as intermediaries between the therapeutic goal and the molecular target, binding to the GTP binding domain of Ras, Rac, and Rho proteins to block their signaling activity, thereby providing a new mechanism to overcome treatment resistance
2Object-generated harmful factors
If the Ras GTP binding domain is targeted, then aberrant signaling pathways are disrupted, but the undruggable nature of the domain prevents effective drug binding
Solution Approach 1:
The patent fundamentally changes the chemical parameters and molecular structure of drug candidates to create compounds capable of binding to the Ras GTP binding domain. The novel chemical structures (Formula I compounds) have specific physicochemical properties that enable them to interact with the previously inaccessible target, transforming an undruggable domain into a viable therapeutic target
Solution Approach 2:
The patent segments the approach to targeting Ras by focusing specifically on the GTP binding domain and developing compounds that selectively interact with this region. By segmenting the therapeutic strategy to target this specific domain with specialized small molecules, the patent overcomes the general undruggability of the Ras protein
3Reliability
If small molecules are designed to bind to the GTP binding domain, then GTP binding is inhibited and signaling pathways are disrupted, but the affinity and selectivity of binding must be optimized
Solution Approach 1:
The patent optimizes the molecular parameters of small compounds (Formula I) to achieve high binding affinity for the Ras GTP binding domain. By carefully adjusting chemical parameters such as molecular weight, functional groups, and structural configuration, the patent achieves reliable and specific binding while managing the complexity of molecular design through systematic structure-activity relationship optimization
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The small molecules effectively inhibit the proliferation of human tumor cell lines, downregulate inflammatory cytokines, and provide therapeutic benefits for cancer, inflammatory diseases, and fibrotic diseases by targeting the Ras and Rho signaling pathways.
Implementation Method 1
small molecules that competitively bind to the GTP binding domain of Ras, Rac, and Rho proteins, inhibiting GTP binding
Data Source
AI summary
Provided herein are methods and compositions for treating cancers, inflammatory diseases, rasopathies, and fibrotic disease involving aberrant Ras superfamily signaling through the binding of compounds to the GTP binding domain of Ras superfamily proteins including, in certain cases, K-Ras and mutants thereof, and a method for assaying such compositions.