KRAS G12D Inhibition via Cyclic Peptide Surface Binding

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Solution Overview

Problem

Current attempts to develop inhibitors for the KRAS oncogene, particularly the KRAS (G12D) mutation, have been unsuccessful due to the difficulty in outcompeting GTP for the KRAS binding pocket and the lack of known allosteric regulatory sites.

Innovation Solution

Cyclic peptides that selectively bind to the KRAS (G12D) oncogenic protein, represented by specific sequences, are developed to inhibit KRAS activity by binding to its surface, thereby circumventing the need for a binding pocket.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional inhibitors are used to target KRAS binding pocket, then inhibition of KRAS activity is attempted, but the difficulty in outcompeting GTP for the binding pocket prevents successful inhibition

Engineering Contradiction:

Improveinhibition efficacyVSAvoidGTP competition

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

Instead of attempting to bind to the KRAS binding pocket (the conventional approach that fails due to GTP competition), the invention inverts the strategy by designing cyclic peptides that bind to the surface of KRAS. This alternative binding approach avoids direct competition with GTP while still achieving inhibition of KRAS oncogenic activity, particularly for the G12D mutant form.

Inventive Principle:

Principle #13The other way round (Inversion)

2Reliability

If cyclic peptides are designed to bind KRAS surface, then selectivity for KRAS (G12D) over wild-type is achieved, but the complexity of designing specific sequences increases

Engineering Contradiction:

Improvebinding selectivityVSAvoidsequence design complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention achieves selectivity for KRAS (G12D) over wild-type KRAS by systematically varying parameters in the cyclic peptide sequence, particularly at positions V1-V5. By changing amino acid residues at these positions and observing their effect on binding affinity and selectivity, the researchers identified specific sequences (such as those containing guanidinophenylalanine and bromophenylalanine) that preferentially bind to the G12D mutant surface, thereby achieving high selectivity through controlled parameter optimization.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11414460B2KRAS-specific capture agents, compositions, and methods of making and using

Publication Date: 2022.08.16 INSTITUTE FOR SYSTEMS BIOLOGY

AI summary

Disclosed are compounds, compositions, and methods involving cyclic peptides that can bind to KRAS (G12D) oncogenic protein. For example, disclosed are cyclic peptides that selectively bind KRAS (G12D) oncogenic protein. Also disclosed are methods of inhibiting KRAS (G12D) oncogenic protein in a cancer cell expressing KRAS (G12D) oncogenic protein. In some forms, the method comprises incubating the cancer cell with any one or more of the disclosed cyclic peptides. In some forms, the method comprises bringing into contact the cancer cell with any one or more of the disclosed cyclic peptides.