KRB-456

KRB-456 is a novel small molecule allosteric inhibitor of the KRAS G12D mutant, a frequent driver in various cancers, particularly pancreatic ductal adenocarcinoma. It functions by binding to a dynamic allosteric pocket within the switch-I/II region of KRAS G12D, interacting with both the GDP-bound (inactive) and GCP-bound (active-like) states. This binding prevents the interaction between KRAS G12D and its downstream effector, RAF1, thereby inhibiting the MAPK (P-MEK) and PI3K/AKT signaling pathways. Preclinical data from patient-derived xenograft (PDX) models of pancreatic cancer indicate that KRB-456 can significantly inhibit tumor growth, including in cases resistant to standard chemotherapy and radiotherapy.