Farnesyltransferase-Mediated Delivery of a Covalent Inhibitor Overcomes Alternative Prenylation to Mislocalize K-Ras

ACS Chemical Biology
Chris J NovotnyKevan M Shokat

Abstract

Mutationally activated Ras is one of the most common oncogenic drivers found across all malignancies, and its selective inhibition has long been a goal in both pharma and academia. One of the oldest and most validated methods to inhibit overactive Ras signaling is by interfering with its post-translational processing and subsequent cellular localization. Previous attempts to target Ras processing led to the development of farnesyltransferase inhibitors, which can inhibit H-Ras localization but not K-Ras due to its ability to bypass farnesyltransterase inhibition through alternative prenylation by geranylgeranyltransferase. Here, we present the creation of a neo-substrate for farnesyltransferase that prevents the alternative prenlation by geranylgeranyltransferase and mislocalizes oncogenic K-Ras in cells.

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Citations

Mar 1, 2019·ChemMedChem·Avick Kumar GhoshWenshe Ray Liu
Nov 20, 2019·International Journal of Molecular Sciences·Hazem AbdelkarimVadim Gaponenko
Aug 18, 2020·Journal of Biomolecular NMR·Christopher B MarshallMitsuhiko Ikura
Apr 3, 2019·International Journal of Molecular Sciences·Paola SavoiaOttavio Cremona
Dec 24, 2017·Cancer Research·Ruth NussinovHyunbum Jang
Mar 27, 2020·Cancer Research·Ian A PriorJames L Hartley
Aug 6, 2019·Cell Chemical Biology·Roger S GoodyDaniel Rauh
Mar 9, 2018·Seminars in Cancer Biology·Keesha E EricksonBoris N Kholodenko
Nov 23, 2020·Current Opinion in Chemical Biology·Ana Losada de la LastraEdward W Tate
Jun 3, 2021·Genes·Alberto Fernández-MedardeEugenio Santos
Oct 27, 2017·ACS Chemical Biology·David M MoffordStephen C Miller
Dec 18, 2021·Molecular Biomedicine·Kulshrestha Ritu Rajkumar

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