Stabilized SOS1 Peptides for KRAS Inhibition
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Solution Overview
Problem
Current therapies are ineffective in targeting KRAS mutations, which are prevalent in various cancers, particularly pancreatic ductal adenocarcinoma, leading to treatment resistance and limited therapeutic options for patients with KRAS-mutant tumors.
Innovation Solution
Development of structurally stabilized peptides that target both wild-type and mutant forms of KRAS by incorporating guanine peptide-nucleic acid monomers, enhancing binding affinity and cytotoxicity in KRAS-driven cancer cells, including the use of internally cross-linked polypeptides that mimic SOS1 to disrupt KRAS activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapies are used to target KRAS mutations, then treatment options are limited, but therapeutic efficacy is poor due to treatment resistance
Solution Approach 1:
The patent uses SOS1 peptide as an intermediary molecule to disrupt the protein-protein interaction between KRAS and its activator SOS1. The stabilized SOS1 peptide binds to SOS1 and prevents it from activating KRAS, thereby blocking the oncogenic signaling pathway without directly targeting the mutated KRAS protein itself.
Solution Approach 2:
The patent employs internal cross-linking (stapling) of the SOS1 peptide to modify its structural parameters. This stapling increases the peptide's thermal stability, protease resistance, and binding affinity for SOS1, transforming it from a labile peptide into a stable therapeutic agent that can effectively inhibit KRAS activation in vivo.
2Stability of the object's composition
If peptide structure is stabilized through internal cross-linking, then binding affinity and stability improve, but molecular complexity increases
Solution Approach 1:
The SOS1 peptide is segmented into specific regions, with cross-linking placed at strategic positions (typically at the N-terminal region) to stabilize the helical structure without interfering with the functional binding interface. This selective segmentation allows stabilization while preserving biological activity.
Solution Approach 2:
The patent creates a composite molecular structure by combining the SOS1 peptide sequence with non-natural amino acid cross-links (staples). This composite structure integrates the biological recognition capabilities of the peptide with the enhanced stability of the synthetic cross-link, achieving both high affinity binding and protease resistance.
3Reliability
If nanomolar binding affinity is achieved, then therapeutic potency increases, but selectivity between wild-type and mutant KRAS becomes challenging
Solution Approach 1:
The SOS1 peptide targets the SOS1 protein itself rather than KRAS directly, making it universally effective against both wild-type and mutant KRAS. Since SOS1 is the activator upstream of KRAS, inhibiting SOS1 blocks KRAS activation regardless of the KRAS mutation status, providing broad-spectrum activity against all KRAS-driven cancers.
Data Source
Figure 1A~1B
Figure 1C
Figure 1D
AI summary
Provided herein are polypeptides containing stabilized therapeutic peptides related to KRAS guanidine exchange factor (SOS1). Also provided are compositions containing these polypeptides and methods of using such peptides in the treatment of cancer that includes administering to a subject one of the polypeptides. This disclosure relates to structurally stabilized therapeutic peptides related to KRAS guanidine exchange factor (SOS1), and methods of using such peptides in the treatment of cancer.