KRAS G12D OFF inhibitor

KRAS G12D OFF inhibitors are a class of small molecule targeted therapies designed to selectively bind and stabilize the inactive, GDP-bound ("OFF") conformation of the KRAS G12D mutant protein. KRAS is a small GTPase that cycles between an active GTP-bound state and an inactive GDP-bound state; the G12D mutation, which is highly prevalent in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, and non-small cell lung cancer (NSCLC), impairs the protein's intrinsic GTPase activity and favors the active state, driving uncontrolled oncogenic signaling. By binding to the Switch II pocket of the GDP-bound form, these inhibitors prevent the exchange of GDP for GTP, thereby trapping the protein in its inactive state and blocking downstream signaling through the MAPK/ERK and PI3K/AKT pathways. Unlike the first generation of KRAS G12C inhibitors that utilize covalent bonding, KRAS G12D OFF inhibitors typically rely on high-affinity non-covalent interactions. Several candidates in this class, such as MRTX1133, have entered clinical evaluation to address the significant unmet need in KRAS G12D-mutated malignancies.

Other names

KRAS G12D GDP-bound inhibitorKRAS G12D inactive-state inhibitorKRAS G12D(GDP) inhibitor