In summary, we report here on the discovery of a novel natural product-inspired small molecule, KRB-456, that binds a dynamic allosteric binding pocket within the switch-I/II region of KRAS G12D, suppresses the levels of KRAS bound to GTP and inhibits the binding of KRAS to RAF1 in human pancreatic cancer cells that harbor KRAS G12D. Here, KRAS is linked to familial pancreatic carcinoma.