Ras-binding domain of Ras effector proteins (RBD)

The Ras-binding domain (RBD) is a conserved protein motif that serves as the primary interaction site for activated Ras GTPases with their downstream effector proteins, such as RAF kinases and Phosphoinositide 3-kinases (PI3K) (Athuluri-Divakar et al., 2016). These interactions are fundamental to the regulation of the Mitogen-Activated Protein Kinase (MAPK) and PI3K/AKT signaling pathways, which control essential cellular processes including proliferation, differentiation, and apoptosis (Zaman et al., 2019). In many human cancers, mutations in RAS genes or over-activation of these pathways drive oncogenesis and resistance to therapy. Rigosertib (ON 01910.Na) is a first-in-class small molecule that functions as a Ras-mimetic, binding directly to the RBDs of RAF and PI3K (Onconova Therapeutics, 2023). By occupying the RBD, rigosertib competitively inhibits the binding of active Ras to these effectors, thereby disrupting the transmission of oncogenic signals. This mechanism of action provides a unique approach to targeting Ras-driven diseases, such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), by simultaneously inhibiting multiple downstream cascades (Navada et al., 2018; PubChem CID 10411248).

Other names

Ras-binding domainRBDRAF Ras-binding domainPI3K Ras-binding domainRas-effector interaction site

Rigosertib acts as a Ras-mimetic that binds to the Ras-binding domains (RBDs) of various Ras effector proteins, including RAF kinases (CRAF, BRAF) and PI3K. By occupying these domains, it competitively inhibits the interaction between activated Ras (GTP-bound Ras) and its effectors, thereby blocking the activation of downstream signaling pathways such as the MAPK/ERK and PI3K/AKT/mTOR pathways (Athuluri-Divakar et al., 2016; Onconova Therapeutics, 2023).