Discovery of UCB9386: A Potent, Selective, and Brain-Penetrant Nuak1 Inhibitor Suitable for In Vivo Pharmacological Studies

  • J Med Chem. 2024 Dec 12;67(23):20879-20910. doi: 10.1021/acs.jmedchem.4c01237.
Karine G Poullennec  1 ,  Eric Jnoff  1 ,  Jan Abendroth  2 ,  Naresh Bhuma  3 ,  Mark Calmiano  4 ,  Laurent Calmus  5 ,  Alvaro Cardenas  1 ,  Jean-Philippe Courade  6 ,  Claude Delatour  1 ,  Adrian Hall  1 ,  Teresa de Haro  1 ,  Silvia L Delker  7 ,  Thierry Demaude  1 ,  Nilesh Gaikwad  8 ,  Dnyaneshwar Ghavate  8 ,  Atul R Gholap  8 ,  Magdalena Kierkowicz  9 ,  Régis Le Mestre  10 ,  Nathalie Van Hijfte  11 ,  Simon Verheijden  12 ,  Katerina Vernerova  9 ,  Veerle De Wever  1 ,  Nivrutti Waghmode  13
Affiliations
  • 1. Chemin du Foriest, UCB, 1420 Braine l'Alleud, Belgium.
  • 2. UCB Seattle, Bainbridge Island, Washington 98110, United States.
  • 3. Illumina Centre, 19 Granta Park, Great Abingdon CB21 6DF, United Kingdom.
  • 4. BenevolentAI, London W1T 5HD, United Kingdom.
  • 5. NovAliX, 240 Parc d'Affaires des Portes, 27100 Val-de-Reuil, France.
  • 6. Discoveric Bio α group, Bahnhofstrasse 1, CH-8808 Pfäffikon (SZ), Switzerland.
  • 7. UCB Boston, Cambridge, Massachusetts 01240, United States.
  • 8. Sai Life Sciences Ltd, IKP Knowledge Park, Genome Valley, Turkapally, Hyderabad 500078, India.
  • 9. UCB, Slough SL1 3WE, United Kingdom.
  • 10. Minoryx Therapeutics, Avenue Jean Mermoz 32, 6041 Charleroi, Belgium.
  • 11. NovAliX SAS, 16 rue d'Ankara, 67000 Strasbourg, France.
  • 12. Janssen Research and Development, Antwerpseweg 15, 2340 Beerse, Belgium.
  • 13. Squadron Life Sciences Pvt Ltd, Bhosari, Pune 411039, India.
PMID: 39588908 DOI: 10.1021/acs.jmedchem.4c01237
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.

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