Pharmacological restoration of GTP hydrolysis by mutant RAS.

ABSTRACT: Approximately 3.4 million patients worldwide are diagnosed each year with cancers that have pathogenic mutations in one of three RAS proto-oncogenes (KRAS, NRAS and HRAS)^1,2. These mutations impair the GTPase activity of RAS, leading to activation of downstream signalling and proliferation^3-6. Long-standing efforts to restore the hydrolase activity of RAS mutants have been unsuccessful, extinguishing any consideration towards a viable therapeutic strategy⁷. Here we show that tri-complex inhibitors-that is, molecular glues with the ability to recruit cyclophilin A (CYPA) to the active state of RAS-have a dual mechanism of action: not only do they prevent activated RAS from binding to its effectors, but they also stimulate GTP hydrolysis. Drug-bound CYPA comp

SUBMITTER: Cuevas-Navarro A 

PROVIDER: S-EPMC11666464 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature