Karine G. Poullennec, Eric Jnoff, Jan Abendroth, Naresh Bhuma, Mark Calmiano, Laurent Calmus*, Alvaro Cardenas, Jean-Philippe Courade, Claude Delatour, Adrian Hall, Teresa de Haro, Silvia L. Delker, Thierry Demaude, Nilesh Gaikwad, Dnyaneshwar Ghavate, Atul R. Gholap, Magdalena Kierkowicz, Régis Le Mestre*, Nathalie Van Hijfte*, Simon Verheijden, Katerina Vernerova, Veerle De Wever, and Nivrutti Waghmode
Journal of Medicinal Chemistry, Article ASAP 2024, published November 26, 2024
Abstract:
Nuak1 (NUAK family SnF1-like kinase-1) is a serine-threonine kinase and a member of the AMPK family. Interest in Nuak1 has increased over the years due to the role it plays in several biological processes, from tumor cell invasion and proliferation to Tau stabilization. Nuak1 is expressed in many cancer cell lines and many reports describe this target as an oncogene, the inhibition of which is hypothesized to be valuable for treating various cancer types including glioma. We report here the discovery of Nuak1 inhibitors originating from HTS hit 9 with excellent selectivity and the subsequent medicinal chemistry optimization program, supported by structural information from the first crystal structures of a Nuak1 chimeric protein which provided insights into the binding modes of our compounds. These efforts yielded a nanomolar cell potent, highly selective and brain penetrant Nuak1 inhibitor UCB9386 (56) suitable for in vivo pharmacological studies for central nervous system (CNS) disorders.
* authors from Novalix
