Macrocyclic KRAS Peptides for Stable Mutant-Selective Inhibition
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Solution Overview
Problem
Current small molecule covalent inhibitors for KRAS mutations, such as G12D and G12V, face challenges due to a lack of suitable surface pockets for docking, and peptide-based modulators with disulfide crosslinks are not ideal in the reducing environment of the cytosol.
Innovation Solution
Development of macrocyclic peptides and peptidomimetics that bind K-Ras with high affinity, stability, and selectivity, including compounds with specific structural formulas that inhibit various K-Ras mutants, particularly G12D, G12C, and G13D, enhancing cellular potency and membrane permeability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule covalent inhibitors are used to target KRAS mutations, then they can achieve covalent binding to the target, but they face challenges due to a lack of suitable surface pockets for docking
Solution Approach 1:
The invention divides the inhibitor into two distinct parts: a macrocyclic peptide portion that binds to the KRAS surface (including switch region and pre-P-loop), and a separate warhead group that provides covalent reactivity. This segmentation allows the molecule to overcome the lack of suitable surface pockets by using the flexible macrocyclic peptide to adapt to the target surface while the warhead provides the necessary covalent binding capability.
Solution Approach 2:
The invention creates a hybrid molecule combining peptide-based macrocyclic structures with small molecule warhead groups. This composite approach integrates the advantages of both peptide flexibility and small molecule reactivity, enabling covalent inhibition of KRAS mutants even in the absence of traditional small molecule binding pockets.
2Adaptability or versatility
If peptide-based modulators with disulfide crosslinks are used, then they can bind to diverse protein epitopes, but they are not ideal in the reducing environment of the cytosol
Solution Approach 1:
The invention changes the chemical parameter of the crosslink from disulfide (which is unstable in reducing environments) to alternative crosslinking chemistries such as stapling, spiroisoxazolidinone, or other non-disulfide crosslinks. This parameter change maintains the structural constraints and binding versatility of cyclic peptides while improving stability in the cytosolic reducing environment.
3Productivity
If conventional inhibitors are used, then they can inhibit KRAS activity, but they lack selectivity against H-Ras and N-Ras
Solution Approach 1:
The invention exploits local structural differences in the KRAS mutant proteins, particularly in the switch regions and pre-P-loop areas that differ between KRAS mutants and wild-type HRAS/NRAS. The macrocyclic peptide is designed to specifically recognize and bind to these locally distinct features of KRAS mutants, achieving selectivity while maintaining inhibitory activity.
4Productivity
If macrocyclic peptides are designed to improve cell membrane permeability, then cellular potency can be enhanced, but molecular complexity increases
Solution Approach 1:
The invention modifies physical-chemical parameters of the macrocyclic peptide including hydrophobicity, charge distribution, and molecular size to optimize cell membrane permeability. These parameter changes are achieved through careful selection of amino acid residues and crosslinking strategies that enhance cellular uptake while controlling molecular complexity.
Data Source
AI summary
The invention provides compounds of Formula (I) or pharmaceutically acceptable salts thereof, wherein the variables are as described herein. The compounds or their pharmaceutically acceptable salts can inhibit mutants of Kirsten rat sarcoma (K-Ras) protein including the G12D mutant and are expected to have utility as therapeutic agents, for example, for treating cancer. The invention also provides pharmaceutical compositions having compounds of Formula (I) or pharmaceutically acceptable salts thereof. Further, the invention provides methods for using the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of cancer and for preparing pharmaceuticals for this purpose.