%0 Journal Article
%A Poorebrahim, Mansour
%A Abazari, Mohammad Foad
%A Moradi, Leila
%A Shahbazi, Behzad
%A Mahmoudi, Reza
%A Kalhor, Hourieh
%A Askari, Hassan
%A Teimoori-Toolabi, Ladan
%T Multi-targeting of K-Ras domains and mutations by peptide and small molecule inhibitors.
%J PLoS Computational Biology
%V 18
%N 4
%@ 1553-734X
%C San Francisco, Calif.
%I Public Library of Science
%M DKFZ-2022-00843
%P e1009962 -
%D 2022
%Z #EA:D122#
%X 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-RasG12D and K-RasG12C 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:35472201
%R 10.1371/journal.pcbi.1009962
%U https://inrepo02.dkfz.de/record/179694