5EAK

Optimization of Microtubule Affinity Regulating Kinase (MARK) Inhibitors with Improved Physical Properties

5EAK の概要

• エントリーDOI: 10.2210/pdb5eak/pdb
• 分子名称: Serine/threonine-protein kinase MARK2, N-[(1S,2R)-2-aminocyclohexyl]-4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide (3 entities in total)
• 機能のキーワード: catalytic domain, protein-serine-threonine kinases, kinase inhibitor, serine-threonine kinases, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane; Peripheral membrane protein: Q7KZI7
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76508.48

構造登録者

Su, H.P. (登録日: 2015-10-16, 公開日: 2016-02-17, 最終更新日: 2024-03-06)

主引用文献

Sloman, D.L.,Noucti, N.,Altman, M.D.,Chen, D.,Mislak, A.C.,Szewczak, A.,Hayashi, M.,Warren, L.,Dellovade, T.,Wu, Z.,Marcus, J.,Walker, D.,Su, H.P.,Edavettal, S.C.,Munshi, S.,Hutton, M.,Nuthall, H.,Stanton, M.G.
Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties.
Bioorg.Med.Chem.Lett., 26:4362-4366, 2016

PubMed Abstract: Inhibition of microtubule affinity regulating kinase (MARK) represents a potentially attractive means of arresting neurofibrillary tangle pathology in Alzheimer's disease. This manuscript outlines efforts to optimize a pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in potency, physical properties and attributes amenable to CNS penetration. A unique cylcyclohexyldiamine scaffold was identified that led to remarkable improvements in potency, opening up opportunities to reduce MW, Pgp efflux and improve pharmacokinetic properties while also conferring improved solubility.

PubMed: 27491711
DOI: 10.1016/j.bmcl.2016.02.003

実験手法

X-RAY DIFFRACTION (2.8 Å)