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Sequence‐Selective Covalent CaaX‐Box Receptors Prevent Farnesylation of Oncogenic Ras Proteins and Impact MAPK/PI3 K Signaling
Author(s) -
Franz Matthias,
Mörchen Britta,
Degenhart Carsten,
Gülden Daniel,
Shkura Oleksandr,
Wolters Dirk,
Koch Uwe,
Klebl Bert,
Stoll Raphael,
Helfrich Iris,
Scherkenbeck Jürgen
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100167
Subject(s) - prenylation , farnesyltransferase , small molecule , biology , biochemistry , sequence (biology) , microbiology and biotechnology , palmitoylation , effector , ras superfamily , cysteine , computational biology , enzyme , gtp'
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.