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

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 properties in mice. We show that genetic knockdown
and pharmacological inhibition of STK3 and STK4 suppress the proliferation
of AML cells in vitro. Thus, SBP-3264 is a valuable chemical probe
for understanding the roles of STK3 and STK4 in AML and is a promising
candidate for further advancement as a potential therapy.