Design and Evaluation of Bivalent K-Ras Inhibitors That Target the CAAX Binding Site and the Acidic Surface of Farnesyltransferase and Geranylgeranyltransferase I.

ABSTRACT: Mutant K-Ras drives cancer through its membrane localization, which requires posttranslational modification by farnesyltransferase (FTase). FTase attaches farnesyl to the K-Ras C-terminal CVIM tetrapeptide, enabling membrane binding. However, K-Ras can also undergo compensatory geranylgeranylation by geranylgeranyltransferase I (GGTase I), making FTase inhibition alone ineffective. Dual inhibition of FTase and GGTase I is necessary to fully block K-Ras localization and its cancer activity. We developed bivalent inhibitors targeting both FTase and GGTase I by binding to the CVIM (C = cysteine, V = valine, I = isoleucine, M = methionine) site and an adjacent acidic surface. A nonthiol CVIM peptidomimetic based on a piperidine scaffold showed potent FTase inhibition (K_i = 2.1 nM) w

SUBMITTER: Horiuchi N 

PROVIDER: S-EPMC12080315 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature