Discovery and Optimization of Selective Inhibitors of Large Tumor Suppressor Kinases LATS1 and 2 for In Vivo Investigation of the Hippo-YAP Pathway in Tissue Regeneration

Large
Tumor Suppressor kinases LATS1 and 2 (LATS1/2) are serine/threonine
kinases and core regulators of the Hippo-YAP pathway. Inhibition of
LATS1/2 promotes nuclear translocation of nonphosphorylated YAP, thereby
initiating a downstream cascade promoting cell proliferation. We set
out to investigate the potential of LATS inhibition as a therapeutic
approach to enhance tissue regeneration and hereby report a structure-guided
optimization of screening hit 1 for potency, binding
efficiency, and physicochemical properties, leading to a highly selective,
cellularly active, and orally available tool compound 7 (NIBR-LTSi) that demonstrated ex vivo target engagement
and in vivo YAP target gene activation in rodents.