Inhibitors of the Hippo Pathway Kinases STK3/MST2 and STK4/MST1 Have Utility for the Treatment of Acute Myeloid Leukemia.

ABSTRACT: Serine/threonine-protein kinases 3 and 4 (STK3 and STK4, respectively) are key components of the Hippo signaling pathway, which regulates cell proliferation and death and provides a potential therapeutic target for acute myeloid leukemia (AML). Herein, we report the structure-based design of a series of pyrrolopyrimidine derivatives as STK3 and STK4 inhibitors. In an initial screen, the compounds exhibited low nanomolar potency against both STK3 and STK4. Crystallization of compound 6 with STK4 revealed two-point hinge binding in the ATP-binding pocket. Further characterization and analysis demonstrated that compound 20 (SBP-3264) specifically inhibited the Hippo signaling pathway in cultured mammalian cells and possessed favorable pharmacokinetic and pharmacodynamic properti

SUBMITTER: Bata N 

PROVIDER: S-EPMC10149138 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature