5EAK

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

Summary for 5EAK

• Entry DOI: 10.2210/pdb5eak/pdb
• Descriptor: 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)
• Functional Keywords: catalytic domain, protein-serine-threonine kinases, kinase inhibitor, serine-threonine kinases, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane; Peripheral membrane protein: Q7KZI7
• Total number of polymer chains: 2
• Total formula weight: 76508.48

Authors

Su, H.P. (deposition date: 2015-10-16, release date: 2016-02-17, Last modification date: 2024-03-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.8 Å)