Bridged Compounds for Selective KRAS G12D Inhibition

Solution Overview

Problem

Current therapies lack effective methods to selectively inhibit the mutated KRAS protein, particularly the KRAS G12D mutation, which is prevalent in pancreatic cancer and other cancers, without affecting the wild-type KRAS protein, making it a challenging target for cancer treatment.

Innovation Solution

Development of bridged compounds that can selectively inhibit the KRAS G12D mutation by binding to the mutated protein or leveraging protein degradation mechanisms, such as using Proteolysis Targeting Chimera (PROTAC) to induce KRAS protein degradation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current therapies are used to target KRAS, then they can address wild-type KRAS function, but they cannot selectively inhibit mutated KRAS G12D protein

Engineering Contradiction:

Improveselectivity of KRAS inhibitionVSAvoidability to treat KRAS-mutated cancers

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies local quality by designing compounds with specific structural features (bridged morpholine or bridged piperazine rings) that create localized interactions with the mutated KRAS G12D protein. These compounds contain specific substituents (R1-R6, R8-R12) that can be optimized to target the unique structural characteristics of the G12D mutation while sparing wild-type KRAS, thereby achieving selective inhibition through localized molecular interactions.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying molecular parameters of the bridged compound structure, including different bridge configurations, substituent types, and molecular properties. By optimizing these parameters, the compounds achieve enhanced selectivity for KRAS G12D over wild-type KRAS, enabling selective inhibition through precise control of molecular characteristics rather than broad-spectrum activity.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If KRAS protein is targeted for inhibition, then cancer progression can be blocked, but wild-type KRAS function in normal cells is compromised

Engineering Contradiction:

Improvecancer treatment efficacyVSAvoidtoxicity to normal cells

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing compounds with specific structural features (bridged morpholine or bridged piperazine rings) that create localized interactions with the mutated KRAS G12D protein. These compounds contain specific substituents (R1-R6, R8-R12) that can be optimized to target the unique structural characteristics of the G12D mutation while sparing wild-type KRAS, thereby achieving selective inhibition through localized molecular interactions.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs intermediary mechanisms by designing compounds that act as molecular mediators between the therapeutic goal (KRAS inhibition) and the biological system. The bridged compounds serve as selective intermediaries that preferentially bind to and inhibit mutated KRAS G12D while allowing wild-type KRAS to maintain its essential functions in normal cells, thus mediating cancer-specific inhibition without broad toxicity.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If PROTAC mechanism is used to induce KRAS degradation, then selective elimination of mutated KRAS can be achieved, but the mechanism complexity increases

Engineering Contradiction:

Improveselectivity of KRAS degradationVSAvoidmechanism complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent employs intermediary mechanisms by designing compounds that act as molecular mediators between the therapeutic goal (KRAS inhibition) and the biological system. The bridged compounds serve as selective intermediaries that preferentially bind to and inhibit mutated KRAS G12D while allowing wild-type KRAS to maintain its essential functions in normal cells, thus mediating cancer-specific inhibition without broad toxicity.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent applies self-service by designing PROTAC compounds that leverage the cell's own protein degradation machinery (ubiquitin-proteasome system) to eliminate mutated KRAS. The bridged compounds with specific structural features recruit cellular E3 ligases to target and degrade KRAS G12D, allowing the biological system to perform the therapeutic function through its inherent mechanisms rather than requiring external degradation pathways.

Inventive Principle:

Principle #25Self-service

Data Source

PatentUS20240140957A1Bridged compounds as KRAS g12d inhibitor and degrader and the use thereof

Publication Date: 2024.05.02 BEONE MEDICINES I GMBH

AI summary

Provided herein are Bridged Compounds having the following structures:wherein R1a, R1b, R1c, R1d, R2a, R2b, R2c, R2d, R3a, R3b, R3c, R3d, R4, R5, R6, R7, R8, m1, m2, m3, n2, n3, n4, q, X1, X2, Y1, Y2, L1 and ring A are as defined herein, compositions comprising an effective amount of a Bridged Compound, and methods for treating or preventing various diseases, e.g., pancreatic cancer, or a condition treatable or preventable by inhibition of the function of KRAS protein. In another aspect, a Bridged Compound is useful for treating or preventing a condition treatable or preventable by inhibition of the function of KRAS protein with G12D mutation. In another aspect, a Bridged Compound is useful for treating or preventing a condition treatable or preventable by inhibition of a RAS/MAPK pathway.