KRAS G12D PROTAC Degrader for Limited Binding Pockets
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Solution Overview
Problem
There is an unmet clinical need for effective KRAS G12D targeted protein degraders due to the lack of distinct binding pockets on the KRAS protein surface and the inability of covalent binding strategies to target the aspartic acid residue at codon 12, limiting the development of inhibitors for this common mutation in colorectal and pancreatic cancers.
Innovation Solution
Development of a KRAS G12D degrader compound, including various stereoisomers and pharmaceutically acceptable salts, designed to target and degrade the KRAS G12D protein through specific binding and degradation pathways, leveraging the potential of PROTAC technology to overcome the challenges of targeting non-druggable targets.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If covalent binding strategies are used to target KRAS, then high affinity binding can be achieved, but the aspartic acid residue at codon 12 in KRAS G12D cannot be targeted
Solution Approach 1:
The patent employs PROTAC technology as an intermediary approach. Instead of directly binding to KRAS G12D, the compound uses a degrader mechanism that recruits E3 ubiquitin ligase to tag KRAS G12D for degradation. This intermediary degradation pathway overcomes the limitation of direct covalent binding to aspartic acid residue, enabling effective targeting of KRAS G12D mutant while maintaining high specificity.
2Reliability
If direct targeting of KRAS protein is attempted, then the therapeutic effect can be achieved, but the smooth surface lacking ideal binding sites makes inhibitor development highly challenging
Solution Approach 1:
The patent uses PROTAC technology as an intermediary system. The compound consists of two functional modules: a KRAS G12D binding module and an E3 ubiquitin ligase binding module connected by a linker. This intermediary degrader approach bypasses the need for traditional small molecule inhibitors that require ideal binding sites, enabling effective targeting of the smooth KRAS surface through a degradation-mediated mechanism.
Solution Approach 2:
The KRAS G12D degrader compound is segmented into distinct functional modules: a KRAS G12D binding module (first molecular unit), an E3 ubiquitin ligase binding module (second molecular unit), and a linker connecting them. This segmentation allows each module to independently perform its function - binding to respective targets and facilitating degradation - overcoming the challenge of developing inhibitors for the smooth KRAS surface.
3Adaptability or versatility
If PROTAC technology is used to target non-druggable targets like KRAS, then the potential therapeutic approach can be realized, but the compound complexity increases
Solution Approach 1:
The PROTAC compound is divided into segmented functional modules: a KRAS G12D binding module, an E3 ubiquitin ligase binding module, and a linker. This segmentation provides modular flexibility, allowing optimization of each module independently while maintaining overall functionality. The modular structure manages complexity by assigning specific functions to discrete units rather than requiring a single complex binding interface.
Solution Approach 2:
The PROTAC compound exhibits multi-functionality by simultaneously binding to KRAS G12D and E3 ubiquitin ligase, recruiting the ubiquitin-proteasome system to degrade the target protein. This universal degrader mechanism can potentially be applied to other non-druggable targets by changing the binding module, while retaining the same degradation pathway, thus managing complexity through a universal platform approach.
Data Source
AI summary
Disclosed in the present invention are a KRAS G12D degradation agent, and a preparation method and use therefor. The KRAS G12D degradation agent in the present invention is a compound as shown in formula I or I', and/or a stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, prodrug, and/or pharmaceutically acceptable salt thereof. The compound provided by the invention can effectively degrade and/or inhibit KRAS G12D protein in cells, and can be used for preparing a drug for treating and/or preventing related diseases or conditions caused by KRAS G12D mediation. G-L-E I G'-L-E I'