Benzimidazole Modulators of Ras Signaling via SOS Binding

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Solution Overview

Problem

Developing effective inhibitors for Ras-driven tumors has been challenging due to the lack of suitable binding pockets on the Ras protein, and existing approaches have not successfully targeted the Ras signaling pathway effectively.

Innovation Solution

Discovery of a binding pocket on the SOS protein within the Ras:SOS:Ras complex, allowing small molecules to bind and alter Ras activity by increasing SOS-mediated nucleotide exchange, thereby modulating Ras signaling.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If small molecules are designed to inhibit Ras directly, then Ras activity can be blocked, but no suitable binding pockets are available on the Ras protein surface

Engineering Contradiction:

ImproveRas inhibition efficacyVSAvoidDrug design feasibility

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent uses SOS as an intermediary target instead of Ras directly. Small molecules bind to the SOS protein's nucleotide binding pocket, enhancing SOS-mediated nucleotide exchange on Ras, which indirectly modulates Ras activity. This approach overcomes the lack of suitable binding pockets on Ras while maintaining therapeutic efficacy.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If Ras activity is completely inhibited, then oncogenic signaling is blocked, but basal signaling cannot be preserved

Engineering Contradiction:

ImproveAnti-cancer efficacyVSAvoidSignaling modulation flexibility

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent changes the parameter of Ras activity modulation from complete inhibition to enhanced nucleotide exchange. By binding to SOS and increasing its nucleotide exchange activity, the compounds promote GDP-GTP exchange on Ras, leading to increased Ras-GTP levels. This parameter change allows selective modulation of oncogenic Ras signaling while preserving basal signaling pathways.

Inventive Principle:

Principle #35Parameter changes

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 perturb Ras signaling in cancer cells, leading to increased Ras-GTP levels and modulation of downstream signaling pathways, offering a novel approach to treat tumors by altering Ras activity without inhibiting basal signaling.

Implementation Method 1

activate nucleotide exchange by binding to a hydrophobic pocket on the SOS protein

Methodology Applied

Scientific EffectHydrophobic interaction: Hydrophobe

Data Source

PatentUS10501421B1Substituted benzimidazoles as modulators of Ras signaling

Publication Date: 2019.12.10 VANDERBILT UNIV

AI summary

Benzimidazole compounds that increase the rate of SOS-mediated nucleotide exchange on Ras by binding to a functionally relevant, chemically tractable pocket on the SOS protein, as part of the Ras:SOS:Ras complex.