SML-8-73-1

SML-8-73-1 is a covalent, guanosine diphosphate–mimetic small molecule that irreversibly inhibits oncogenic KRAS G12C by targeting the guanine nucleotide–binding (active) site. It is a GDP derivative bearing an electrophilic chloroacetamide group on the β-phosphate that forms a covalent bond with cysteine 12 in the P-loop of KRAS G12C, locking the protein in an inactive, GDP-like conformation and preventing productive interaction with downstream effectors such as RAF and PI3K.[1][3][7][10] Biochemical and structural studies show that SML-8-73-1 is highly selective for KRAS G12C over other small GTPases and can compete with millimolar concentrations of GTP/GDP for the nucleotide-binding pocket, but its two negatively charged phosphate groups severely limit cell permeability, so it has mainly been used as a chemical probe alongside more cell-permeable “caged” prodrugs (e.g., SML-10-70-1) and improved analogs in preclinical research on RAS-targeted therapy.[1][3][5][6][8][10][11]

Other names

SML-8-73-1SML8-73-1SML 8-73-1