Heterocyclic NRAS G12D Binders for Direct Mutant Signal Inhibition
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for effective compounds and methods to treat RAS G12D-mediated diseases, particularly NRAS G12D-mediated diseases, as current therapies targeting RAS mutants have shown limited impact and toxicity issues.
Innovation Solution
Development of heterocyclic compounds, including those of Formula I and Formula IC, which can inhibit NRAS G12D function by directly targeting the mutant RAS proteins, offering a new approach to treat diseases such as NRAS G12D-mediated acute myeloid leukemia (AML) and malignant melanoma.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If upstream targets (RTKs, SHP2, SOS) are inhibited, then RAS signaling is blocked, but treatment impact is limited
Solution Approach 1:
The patent introduces a heterocyclic compound as an intermediary substance that directly binds to and inhibits mutant RAS proteins (KRAS G12C, NRAS G12D, HRAS Q61L). This intermediary approach bypasses the ineffective upstream target inhibition by delivering the inhibitory action directly to the RAS protein itself, thereby achieving reliable treatment impact where previous upstream inhibitors failed.
2Object-affected harmful factors
If downstream proteins (MEK, RAF, PI3K) are regulated, then RAS signaling is controlled, but toxicity issues arise
Solution Approach 1:
The patent applies local quality by designing heterocyclic compounds with specific structural features (Formula I with particular substituent patterns at positions R1-R11) that enable selective binding to mutant RAS proteins while sparing wild-type RAS and other downstream proteins. This localized specificity at the molecular binding interface achieves reliable signal control in mutant-driven cancers without the broad toxicity associated with downstream protein regulation.
Solution Approach 2:
The patent utilizes parameter changes by modifying the chemical structure of the heterocyclic compounds (varying substituents R1-R11, ring structures J, X, Y, Z) to optimize binding affinity and selectivity for mutant RAS proteins. These structural parameter adjustments enable the compounds to distinguish between mutant and wild-type RAS, achieving effective signal control with reduced off-target toxicity.
3Reliability
If farnesyl transferase inhibitors are used, then RAS membrane attachment is prevented, but activation is not blocked
Solution Approach 1:
The patent applies preliminary action by designing heterocyclic compounds that pre-bind to the mutant RAS protein at the inactive GDP-bound state, stabilizing this inactive conformation and preventing subsequent GTP exchange and activation. This preliminary binding action occurs before activation can occur, effectively blocking the致癌 process at an earlier stage than membrane attachment prevention alone could achieve.
Data Source
AI summary
Disclosed herein are compounds, and salts thereof, which inhibit targeted NRAS mutants, pharmaceutical formulations, and methods of treatment of NRAS-mediated diseases, such as certain cancers.