KRAS G12C Inhibitors Binding GDP and GTP States
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Solution Overview
Problem
Current KRAS G12C inhibitors primarily target the GDP-bound form of KRAS, leading to limited efficacy and rapid resistance in cancer treatment, especially in colorectal cancer.
Innovation Solution
Development of compounds that can bind and inhibit both the GDP- and GTP-bound forms of KRAS G12C, thereby providing improved inhibition of the GTP-bound form.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current KRAS G12C inhibitors (AMG 510, MRTX849) are used to treat cancer, then inhibition of GDP-bound KRAS is achieved, but inhibition of GTP-bound KRAS is insufficient leading to rapid resistance
Solution Approach 1:
The patent applies universality by designing a compound that performs multiple functions: it binds to and inhibits both the GDP-bound and GTP-bound forms of KRAS G12C. This multi-functional capability allows the single compound to address both inactive and active states of the target protein, preventing resistance mechanisms that rely on GTP-bound KRAS signaling.
Solution Approach 2:
The patent employs parameter changes by modifying the chemical structure to alter binding characteristics. Specifically, the compound is designed with structural features that enable it to recognize and bind to KRAS in both nucleotide-bound states, changing the binding parameters from state-specific to state-independent inhibition.
2Reliability
If cancer cells increase signaling through RTKs to overcome inhibitor treatment, then GTP-bound KRAS increases, but current inhibitors cannot effectively bind to this form
Solution Approach 1:
The compound achieves universality by being effective against both GDP-bound and GTP-bound KRAS states. This allows it to counteract resistance mechanisms where cancer cells upregulate GTP-bound KRAS through increased RTK signaling, as the compound can still bind and inhibit the GTP-bound form.
Solution Approach 2:
The patent applies preliminary anti-action by designing a compound that anticipates and prevents resistance mechanisms before they occur. By being capable of binding to GTP-bound KRAS from the outset, the compound pre-empts the resistance pathway where cells would otherwise increase GTP-bound KRAS levels to escape inhibition.
Data Source
AI summary
The present disclosure provides compounds and methods useful in the treatment and suppression of cancer, for example, useful for treating or suppressing cancers characterized by KRAS G12C. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.