Bivalent KRAS Inhibitor Compounds for Smooth-Surface Binding
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Solution Overview
Problem
Existing KRas inhibitors face challenges due to the smooth surface of the Ras protein lacking obvious grooves or pockets for binding small-molecule inhibitors, and their high affinity for guanine nucleotides, making them an 'undruggable' target in cancer drug development.
Innovation Solution
Development of novel inhibitor compounds with structural innovations that demonstrate enhanced inhibitory activity against KRas mutant proteins, offering improved pharmacokinetic properties, reduced toxicity, and favorable safety profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small-molecule inhibitors are designed to bind to Ras protein, then inhibitory activity is desired, but the smooth surface of Ras lacking grooves or pockets makes binding difficult
Solution Approach 1:
The patent extends the binding interface from 2D surface binding to 3D pocket formation by using a bivalent structure where two monomer units connect through a linker to form a composite molecule that can simultaneously engage multiple regions of the Ras protein, effectively creating a binding pocket where none naturally exists
Solution Approach 2:
The patent constructs a composite inhibitor molecule composed of two monomer units (each containing a core structure with specific substituents) connected by a linker, creating a bivalent composite that combines the advantages of monomeric simplicity with the binding affinity of multivalent structures
2Reliability
If KRas inhibitors are developed to target mutant proteins, then therapeutic efficacy is improved, but toxicity and side effects increase
Solution Approach 1:
The patent introduces specific substituent groups at defined positions on the core structure (R1-R6 substituents on the bicyclic ring system, R7-R8 on the aromatic ring) to create local chemical features that enhance selective binding to mutant KRas while minimizing off-target effects and toxicity
Solution Approach 2:
The patent systematically varies substituent parameters (different R groups, linker lengths and compositions) to optimize the balance between therapeutic efficacy and safety profile, adjusting molecular properties to achieve selective inhibition with reduced toxicity
3Reliability
If existing KRas inhibitors are used, then some inhibitory activity is achieved, but pharmacokinetic properties are suboptimal
Solution Approach 1:
The patent modifies key molecular parameters including molecular weight, lipophilicity, and hydrogen bonding capacity by selecting specific substituents and linker compositions to improve oral bioavailability, metabolic stability, and tissue penetration while maintaining inhibitory activity
Data Source
AI summary
The present invention provides compounds with the structure of formula (I) that can be used as KRAS inhibitors, pharmaceutical compositions containing these compounds, methods for preparing these compounds, and uses of these compounds in the treatment of cancer.