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<sub>p,u,ub</sub>) of 2.29) that displays no CDK2 activity, applicable for CNS pharmacological studies.
Authors
- Helen K. Boffey (ORCID: https://orcid.org/0000-0001-5088-4615)
- Henriëtte M. G. Willems (ORCID: https://orcid.org/0000-0001-7196-5975)
- Helen E. Scott
- David Winpenny
- Gregory G. Aldred (ORCID: https://orcid.org/0009-0007-4974-0818)
- Jonathan H. Clarke (ORCID: https://orcid.org/0000-0002-4079-5333)
- Stephen P. Andrews (ORCID: https://orcid.org/0000-0001-6021-6899)
- John Skidmore (ORCID: https://orcid.org/0000-0001-9108-7858)
Institutions
- University of Cambridge (GB)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-09-10
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00467
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00