Covalent KRAS Inhibitors Locking Switch II
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Solution Overview
Problem
Current treatments for cancer, particularly those targeting KRAS, HRAS, or NRAS G12C mutations, face challenges in effectively inhibiting these proteins due to their stability and signaling persistence, leading to prolonged cell growth and division, which contributes to cancer development.
Innovation Solution
Development of compounds that can modulate G12C mutant KRAS, HRAS, or NRAS proteins by forming a covalent bond with the cysteine residue at position 12, locking the switch II into an inactive state and disrupting downstream signaling, thereby inhibiting cell proliferation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used to target KRAS, HRAS, or NRAS G12C mutations, then some inhibition effect is achieved, but the proteins maintain stability and signaling persistence leading to prolonged cell growth and division
Solution Approach 1:
The compound performs preliminary action by forming a covalent bond with the cysteine residue at position 12 of the RAS protein before the protein can engage in prolonged signaling. This pre-emptive covalent attachment prevents the protein from maintaining its active conformation and interacting with downstream effectors, thereby blocking the signaling persistence that conventional non-covalent inhibitors fail to prevent
Solution Approach 2:
The invention changes the binding parameter from reversible (non-covalent) to irreversible (covalent) interaction. By introducing a covalent bond between the compound and the cysteine residue, the duration of inhibition is extended from transient to permanent until protein degradation occurs, fundamentally altering the kinetic parameters of inhibitor-protein interaction to eliminate signaling persistence
2Stability of the object's composition
If RAS protein maintains high stability, then protein structure is preserved, but signaling persists leading to prolonged cell growth and division
Solution Approach 1:
The compound applies local quality change by specifically targeting and modifying only the cysteine residue at position 12 within the otherwise stable RAS protein structure. The covalent modification is localized to this single residue, which is sufficient to disrupt the switch II region and prevent active conformation formation, thereby eliminating the harmful signaling function while leaving the rest of the protein structure intact
Solution Approach 2:
The invention converts the normally harmful persistence of RAS protein stability into a benefit by using the stable cysteine residue at position 12 as a permanent anchoring point for the inhibitor. The very stability that allows RAS to maintain prolonged signaling is exploited to create a stable covalent bond with the compound, ensuring long-lasting inhibition without requiring the protein to be degraded
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 compounds effectively inhibit the activity of G12C mutant KRAS, HRAS, or NRAS proteins, potentially leading to therapeutic benefits in treating cancers mediated by these mutations by reducing cell growth and division.
Implementation Method 1
capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutant protein
Data Source
AI summary
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I):or a pharmaceutically acceptable salt, stereoisomer, isotopic form or prodrug thereof, wherein R1, R2a, R2b, R2c, R3a, R3b, R4a, R4b, L1, L2, E, X, Y, Z, m1 and m2 are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.