Rat sarcoma virus GTPase (RAS) (RAS)

The GTP-bound RAS state represents the active “ON” conformation of the Rat sarcoma virus (RAS) family of small GTPases, which includes the isoforms KRAS, HRAS, and NRAS (UniProt P01116, P01112, P01111) [1]. In this state, RAS proteins function as molecular switches that transmit signals from cell surface receptors to downstream effector pathways, such as the MAPK/ERK and PI3K/AKT pathways, to regulate cell growth, differentiation, and survival (National Cancer Institute) [2]. Mutations in RAS genes are among the most common drivers in human oncology, frequently occurring at codons 12, 13, or 61, which stabilize the GTP-bound state by impairing intrinsic and GAP-mediated GTP hydrolysis (PubMed: 32111600) [3]. While historical drug discovery efforts focused on the inactive GDP-bound state (RAS-OFF), modern therapeutic approaches are increasingly targeting the active GTP-bound state (RAS-ON) to address a wider spectrum of mutations and wild-type RAS activity (Revolution Medicines) [4]. These “RAS(ON)” inhibitors often employ a tri-complex mechanism, where the drug binds both the active RAS protein and an abundant intracellular chaperone, such as Cyclophilin A, to sterically block interactions with downstream effectors (Nature, 2023) [5]. This strategy is currently being evaluated in clinical trials for various solid tumors, offering a potential breakthrough for patients with RAS-driven cancers that were previously considered undruggable (ClinicalTrials.gov: NCT05379985) [6].

Other names

Active RASRAS(ON)GTP-bound RASKRASHRASNRASp21 RAS

Inhibitors of the GTP-bound RAS state typically function by binding directly to the active conformation of the RAS protein. A prominent mechanism involves the formation of a tri-complex between the inhibitor, the active RAS-GTP molecule, and an intracellular chaperone protein such as Cyclophilin A. This tri-complex sterically occludes the effector-binding interface of RAS, preventing its interaction with downstream signaling proteins like RAF, PI3K, and RALGEF, thereby halting oncogenic signal transduction.