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000179694 1001_ $$0P:(DE-He78)081f0df0551762b7dbb2faabe23023b5$$aPoorebrahim, Mansour$$b0$$eFirst author$$udkfz
000179694 245__ $$aMulti-targeting of K-Ras domains and mutations by peptide and small molecule inhibitors.
000179694 260__ $$aSan Francisco, Calif.$$bPublic Library of Science$$c2022
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000179694 520__ $$aK-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.
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000179694 7001_ $$aAbazari, Mohammad Foad$$b1
000179694 7001_ $$aMoradi, Leila$$b2
000179694 7001_ $$aShahbazi, Behzad$$b3
000179694 7001_ $$aMahmoudi, Reza$$b4
000179694 7001_ $$00000-0003-0715-294X$$aKalhor, Hourieh$$b5
000179694 7001_ $$00000-0002-2285-2592$$aAskari, Hassan$$b6
000179694 7001_ $$00000-0002-6588-9774$$aTeimoori-Toolabi, Ladan$$b7
000179694 773__ $$0PERI:(DE-600)2193340-6$$a10.1371/journal.pcbi.1009962$$gVol. 18, no. 4, p. e1009962 -$$n4$$pe1009962 -$$tPLoS Computational Biology$$v18$$x1553-734X$$y2022
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