Discovery of KRB-456, a KRAS G12D Switch-I/II Allosteric Pocket Binder That Inhibits the Growth of Pancreatic Cancer Patient-derived Tumors.

ABSTRACT: Currently, there are no clinically approved drugs that directly thwart mutant KRAS G12D, a major driver of human cancer. Here, we report on the discovery of a small molecule, KRB-456, that binds KRAS G12D and inhibits the growth of pancreatic cancer patient-derived tumors. Protein nuclear magnetic resonance studies revealed that KRB-456 binds the GDP-bound and GCP-bound conformation of KRAS G12D by forming interactions with a dynamic allosteric binding pocket within the switch-I/II region. Isothermal titration calorimetry demonstrated that KRB-456 binds potently to KRAS G12D with 1.5-, 2-, and 6-fold higher affinity than to KRAS G12V, KRAS wild-type, and KRAS G12C, respectively. KRB-456 potently inhibits the binding of KRAS G12D to the RAS-binding domain (RBD) of RAF1 as demonstrated by GS

SUBMITTER: Kazi A 

PROVIDER: S-EPMC10754035 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature