Sequence‐Selective Covalent CaaX‐Box Receptors Prevent Farnesylation of Oncogenic Ras Proteins and Impact MAPK/PI3 K Signaling. (19th May 2021)

• Record Type: Journal Article
• Authors: Franz, Matthias; Mörchen, Britta; Degenhart, Carsten; Gülden, Daniel; Shkura, Oleksandr; Wolters, Dirk; Koch, Uwe; Klebl, Bert; Stoll, Raphael; Helfrich, Iris; Scherkenbeck, Jürgen
• Is Part Of: ChemMedChem. Volume 16:Number 16(2021)
• Page Start: 2504
• Page End: 2514
• Publication Date: 2021-05-19
• Subjects: Ras protein -- K-Ras4B -- molecular recognition -- CaaX-box -- covalent inhibitor; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202100167
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Oncogenic Ras proteins are implicated in the most common life‐threatening cancers. Despite intense research over the past two decades, the progress towards small‐molecule inhibitors has been limited. One reason for this failure is that Ras proteins interact with their effectors only via protein‐protein interactions, which are notoriously difficult to address with small organic molecules. Herein we describe an alternative strategy, which prevents farnesylation and subsequent membrane insertion, a prerequisite for the activation of Ras proteins. Our approach is based on sequence‐selective supramolecular receptors which bind to the C‐terminal farnesyl transferase recognition unit of Ras and Rheb proteins and covalently modify the essential cysteine in the so‐called CaaX‐box. Abstract : Thinking inside the (CaaX) box : Despite intense research, the progress towards small‐molecule inhibitors, targeting specific protein‐protein interaction sites of oncogenic Ras proteins, has been limited. A different concept is based on sequence‐selective supramolecular receptors which covalently modify the C‐terminal CaaX‐box and prevent activation of Ras proteins.