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

## TL;DR

Scientists developed new NUAK1 inhibitors that are potent, selective, and can cross the blood-brain barrier, making them promising for treating neurodegenerative diseases.

## Contribution

The development of ARUK2010694 and ARUK2010489, two novel NUAK1 inhibitors with improved selectivity and brain penetration.

## Key findings

- ARUK2010694 is a potent and selective NUAK1 inhibitor with improved mouse plasma half-life.
- ARUK2010489 is a brain-penetrant NUAK1 inhibitor with a Kp,u,ub ratio of 2.29 and no CDK2 activity.

## Abstract

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 (Kp,u,ub) of 2.29)
that displays no CDK2 activity, applicable for CNS pharmacological
studies.