Blocking C-terminal processing of KRAS4b via a direct covalent attack on the CaaX-box cysteine.

ABSTRACT: RAS is the most frequently mutated oncogene in cancer. RAS proteins show high sequence similarities in their G-domains but are significantly different in their C-terminal hypervariable regions (HVR). These regions interact with the cell membrane via lipid anchors that result from posttranslational modifications (PTM) of cysteine residues. KRAS4b is unique as it has only one cysteine that undergoes PTM, C185. Small molecule covalent modification of C185 would block any form of prenylation and subsequently inhibit attachment of KRAS4b to the cell membrane, blocking its biological activity. We translated this concept to the discovery and development of disulfide tethering screen hits into irreversible covalent modifiers of C185. These compounds inhibited proliferation of KRAS4b-driven

SUBMITTER: Maciag AE 

PROVIDER: S-EPMC12088381 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature