8UOJ

Crystal structure of human NUAK1-MARK3 kinase domain chimera bound with azepane (R)-#50 small molecule inhibitor

8UOJ の概要

• エントリーDOI: 10.2210/pdb8uoj/pdb
• 分子名称: MAP/microtubule affinity-regulating kinase 3, (6M)-4-{[(2R)-azepan-2-yl]methyl}-6-[(4R)-imidazo[1,2-a]pyridin-3-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: kinase, serine/threonine-protein kinase, nuak1, mark3, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38794.26

構造登録者

Delker, S.L.,Abendroth, J.,Mayclin, S.J. (登録日: 2023-10-19, 公開日: 2024-11-06, 最終更新日: 2024-12-25)

主引用文献

Poullennec, K.G.,Jnoff, E.,Abendroth, J.,Bhuma, N.,Calmiano, M.,Calmus, L.,Cardenas, A.,Courade, J.P.,Delatour, C.,Hall, A.,de Haro, T.,Delker, S.L.,Demaude, T.,Gaikwad, N.,Ghavate, D.,Gholap, A.R.,Kierkowicz, M.,Le Mestre, R.,Van Hijfte, N.,Verheijden, S.,Vernerova, K.,De Wever, V.,Waghmode, N.
Discovery of UCB9386: A Potent, Selective, and Brain-Penetrant Nuak1 Inhibitor Suitable for In Vivo Pharmacological Studies.
J.Med.Chem., 67:20879-20910, 2024

PubMed 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 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 () suitable for pharmacological studies for central nervous system (CNS) disorders.

PubMed: 39588908
DOI: 10.1021/acs.jmedchem.4c01237

実験手法

X-RAY DIFFRACTION (1.6 Å)