Quinazoline Compounds Covalently Locking KRAS G12C
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for cancer, particularly those targeting KRAS, HRAS, or NRAS G12C mutations, face challenges in effectively inhibiting the proteins due to their stability and signaling persistence, leading to prolonged cell growth and division, which is a common event in human tumorigenesis.
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, potentially locking the protein into an inactive state and disrupting downstream signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cancer treatments targeting RAS proteins are used, then some inhibition effect is achieved, but the proteins remain stable and continue signaling, leading to prolonged cell growth and division
Solution Approach 1:
The compound is designed to preemptively form a covalent bond with the cysteine residue at position 12 of the RAS protein before the protein can engage in prolonged signaling activity. This preliminary covalent modification locks the protein in an inactive conformation, preventing subsequent signaling events and effectively stopping the cell growth promotion cycle before it can persist
Solution Approach 2:
The invention changes the chemical state of the RAS protein by forming a covalent bond with the cysteine residue, transforming the protein from a dynamic signaling molecule capable of repeated activation cycles into a permanently modified, inactive form. This parameter change (from reversible binding to irreversible covalent bonding) fundamentally alters the duration and effectiveness of protein inhibition
2Measurement precision
If small molecules are used to target KRAS G12C mutation, then selective binding to the mutant protein is achieved, but the stability of the protein and persistence of signaling remain challenges
Solution Approach 1:
The compound is designed with specific local chemical properties (electrophilic moiety) that target the unique cysteine residue at position 12 created by the G12C mutation. This local quality (electrophilic reactivity) allows selective binding to the mutant protein's specific structural feature while the overall molecular structure ensures selective recognition of the mutant conformation, achieving both specificity and complete signal inhibition
Solution Approach 2:
The compound combines multiple functional elements: a core structure that recognizes and binds selectively to the G12C mutant conformation, and an electrophilic moiety that forms a covalent bond with the cysteine residue. This composite structure integrates reversible recognition (for specificity) with irreversible bonding (for complete inhibition), resolving the contradiction between selective binding and complete signal suppression
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, offering a therapeutic approach to treat cancers mediated by these mutations by stabilizing the proteins in an inactive state, thereby reducing cell proliferation.
Implementation Method 1
the compounds act as electrophiles which are 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 or prodrug thereof, wherein R1, R2a, R2b, R2c, R3a, R3b, R4a, R4b, R5a, R5b, R6, A, G1, G2, L1, L2, m1, m2, n, X and E are as defined herein, and wherein at least one of R3a, R3b, R4a or R4b is not H. 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.