Sequence‐Selective Covalent CaaX‐Box Receptors Prevent Farnesylation of Oncogenic Ras Proteins and Impact MAPK/PI3 K Signaling

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.

Synthesis, Biological Evaluation, and Binding Mode of a New Class of Oncogenic K‐Ras4b Inhibitors

“…Over the past three decades several strategies to inactivate oncogenic K-Ras4B have been investigated with rather limited success. [11][12][13][14][15][16][17] Only recently, a first direct Ras inhibitor (AMG510, Sotorasib) which targets (GDP)K-Ras4B G12C covalently has entered the market. [18][19][20] MRTX1133 (5), another structurally related compound, is currently in clinical development as a non-covalent G12D Ras-inhibitor of the SII-site.…”

“…Over the past three decades several strategies to inactivate oncogenic K‐Ras4B have been investigated with rather limited success [11–17] . Only recently, a first direct Ras inhibitor (AMG510, Sotorasib) which targets (GDP)K‐Ras4B G12C covalently has entered the market [18–20] .…”