Development of Purine and Pyrrolopyrimidine Scaffolds as Potent, Selective, and Brain Penetrant NUAK1 Inhibitors

NUAK1 is a protein kinase with various cellular functions including cell proliferation, migration and adhesion. NUAK1 has also been implicated in tau phosphorylation and stabilization leading to interest in this kinase as a therapeutic target for neurodegenerative disease. Herein, we describe the optimization of the CDK2 inhibitor NU6140 to the potent and selective NUAK1 inhibitor ARUK2010694, with a significantly improved mouse plasma half-life. Further development of this series also led to the discovery of ARUK2010489, a highly brain penetrant NUAK1 inhibitor (unbound brain/plasma ratio in mice (K_p,u,ub) of 2.29) that displays no CDK2 activity, applicable for CNS pharmacological studies.