Discovery of\nUCB9386: A Potent, Selective, and Brain-Penetrant\nNuak1 Inhibitor Suitable for <i>In Vivo</i> Pharmacological\nStudies

Nuak1 (NUAK family SnF1-like kinase-1) is a serine-threonine\nkinase\nand a member of the AMPK family. Interest in Nuak1 has increased over\nthe years due to the role it plays in several biological processes,\nfrom tumor cell invasion and proliferation to Tau stabilization. Nuak1\nis expressed in many cancer cell lines and many reports describe this\ntarget as an oncogene, the inhibition of which is hypothesized to\nbe valuable for treating various cancer types including glioma. We\nreport here the discovery of Nuak1 inhibitors originating from HTS\nhit <b>9</b> with excellent selectivity and the subsequent medicinal\nchemistry optimization program, supported by structural information\nfrom the first crystal structures of a Nuak1 chimeric protein which\nprovided insights into the binding modes of our compounds. These efforts\nyielded a nanomolar cell potent, highly selective and brain penetrant\nNuak1 inhibitor UCB9386 (<b>56</b>) suitable for <i>in\nvivo</i> pharmacological studies for central nervous system (CNS)\ndisorders.