Fendiline Derivatives Inhibit KRAS Membrane Localization
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Solution Overview
Problem
Current therapies lack potent and selective inhibitors for KRAS plasma membrane localization, which is crucial for cancer treatment, as existing inhibitors face challenges with toxicity and non-specific targeting of other GTPases.
Innovation Solution
Development of novel fendiline derivatives, such as compounds NY0244, NY0331, and NY0335, which modulate KRAS activity by inhibiting its plasma membrane localization with nanomolar potencies and show promise in suppressing oncogenic KRAS-driven cancer cell proliferation without vasodilatory effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If fendiline derivatives are used to inhibit KRAS plasma membrane localization, then anticancer efficacy is improved, but selectivity against other prenymlated GTPases deteriorates
Solution Approach 1:
The patent applies local quality by introducing specific substituent patterns at defined positions on the fendiline core structure. Different substituents (electron-withdrawing or electron-donating groups) are placed at specific positions (R1-R6) to create localized electronic and steric environments that enhance binding affinity for KRAS while reducing off-target effects on other prenymlated GTPases.
Solution Approach 2:
The patent systematically varies chemical parameters including substituent types (halogens, alkyl groups, heterocycles), substituent positions, and molecular geometry to optimize the balance between KRAS inhibition potency and selectivity. This includes modifying the N1 and N4 substituents on the fendiline core to achieve desired pharmacological properties.
2Productivity
If potent KRAS inhibitors are developed, then cancer cell proliferation is suppressed, but side effects such as vasodilatory effects increase
Solution Approach 1:
The patent extracts and eliminates the vasodilatory activity component from the fendiline molecule while preserving the KRAS-inhibiting pharmacophore. By modifying the N1 substituent and introducing specific groups at R2-R6 positions, the invention removes the calcium channel blocking activity that causes vasodilation, thereby isolating the anticancer efficacy from the harmful side effects.
Solution Approach 2:
The patent segments the pharmacological activities by separating the KRAS-binding functionality from the vasodilatory functionality. The modified fendiline structure maintains the core elements necessary for KRAS interaction while removing or modifying the portions responsible for calcium channel blockade, achieving functional segmentation of therapeutic and adverse effects.
Data Source
AI summary
The invention relates generally to the following novel fendiline derivatives, and the preparation and use thereof: Formula I (I) and Formula II (II)