Identification and Characterization of Novel Small-Molecule Enhancers of the CUL3^LZTR1 E3 Ligase KRAS Complex.

ABSTRACT: The RAS family of GTPases is among the most frequently mutated proteins in human cancer, creating a high clinical demand for therapies that counteract their signaling activity. An important layer of regulation that could be therapeutically exploited is the proteostatic regulation of the main RAS GTPases KRAS, NRAS, and HRAS, as well as the closely related members, MRAS and RIT1, by the leucine zipper-like transcriptional regulator 1 cullin 3 RING E3 ubiquitin ligase complex (CUL3^LZTR1). Genetic inactivation of LZTR1, as observed in different cancer entities and Noonan syndrome leads to enhanced RAS GTPase abundance and altered MAPK pathway activation state. Novel therapeutic approaches to interfere with hyperactive RAS signaling, thereby complementing existing treatments,

SUBMITTER: Piech S 

PROVIDER: S-EPMC11420953 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature