Multi-targeting of K-Ras domains and mutations by peptide and small molecule inhibitors

K-Ras activating mutations are significantly associated with tumor progression and aggressive metastatic behavior in various human cancers including pancreatic cancer. So far, despite a large number of concerted efforts, targeting of mutant-type K-Ras has not been successful. In this regard, we aimed to target this oncogene by a combinational approach consisting of small peptide and small molecule inhibitors. Based on a comprehensive analysis of structural and physicochemical properties of predominantly K-Ras mutants, an anti-cancer peptide library and a small molecule library were screened to simultaneously target oncogenic mutations and functional domains of mutant-type K-Ras located in the P-loop, switch I, and switch II regions. The selected peptide and small molecule showed notable binding affinities to their corresponding binding sites, and hindered the growth of tumor cells carrying K-Ras(G12D) and K-Ras(G12C) mutations. Of note, the expression of K-Ras downstream genes (i.e., CTNNB1, CCND1) was diminished in the treated Kras-positive cells. In conclusion, our combinational platform signifies a new potential for blockade of oncogenic K-Ras and thereby prevention of tumor progression and metastasis. However, further validations are still required regarding the in vitro and in vivo efficacy and safety of this approach. Author summaryK-Ras activating mutations are associated with tumor progression and aggressive metastatic behavior in cancers. We aimed to target this mutated protein as an oncogene with small peptides and small molecules. The selected peptide and small molecules by computational methods showed notable binding affinities to mutated and oncogenic K-Ras. Also, they hindered the proliferation of pancreatic tumor cells. These compounds diminished the expression of downstream genes to mutant K-Ras too. Our combinatorial approach introduces new candidates for blockade of oncogenic K-Ras which is observed in many types of cancer. The effect of these compounds should be validated by further in vitro and in vivo analysis.

Automated summary

K-Ras activating mutations are associated with tumor progression and metastasis. We aimed to target this mutated protein using small peptides and small molecules. Through computational methods, we selected peptides and small molecules that showed strong binding affinity to mutated and oncogenic K-Ras. These compounds hindered the growth of pancreatic tumor cells and reduced the expression of downstream genes. Our combinatorial approach introduces new potential candidates for blocking oncogenic K-Ras in various cancers. Further in vitro and in vivo analysis is needed to validate the efficacy and safety of these compounds.