RAS GTPase (RAS) (RAS)

RAS proteins (KRAS, HRAS, and NRAS) are small GTPases that function as binary molecular switches, relaying signals from extracellular receptors to intracellular pathways like MAPK and PI3K to regulate cell growth and survival (Source: UniProt, P01116). In their normal state, they cycle between an active GTP-bound form and an inactive GDP-bound form, a process tightly regulated by Guanine Nucleotide Exchange Factors (GEFs) and GTPase-Activating Proteins (GAPs) (Source: NIH, National Cancer Institute). Oncogenic mutations, predominantly at positions G12, G13, or Q61, disrupt this cycle by impairing GTP hydrolysis, resulting in constitutive signaling that drives approximately 30% of all human cancers (Source: PubMed, PMID: 33408225). While long deemed undruggable due to a lack of traditional small-molecule binding pockets, the discovery of a cryptic pocket in the KRAS G12C mutant enabled the development of the first FDA-approved RAS inhibitors, Sotorasib and Adagrasib (Source: Nature, doi:10.1038/s41586-021-03596-8). Current therapeutic strategies focus on expanding coverage to other mutations like G12D and overcoming resistance mechanisms such as secondary RAS mutations or upstream pathway reactivation (Source: PubMed, PMID: 34108715).

Other names

KRASHRASNRASp21 RasTransforming protein p21Rat sarcoma virus homolog

Covalent inhibition of the KRAS G12C mutant protein by locking it in the inactive GDP-bound state; inhibition of post-translational modifications like farnesylation to prevent membrane localization; competitive inhibition of effector binding.