ISDA: 5EAK

Deposition Date 2015-10-16

Release Date 2016-02-17

Last Version Date 2024-03-06

Entry Detail

PDB ID:

5EAK

Keywords:

TRANSFERASE/TRANSFERASE INHIBITOR

Title:

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

Biological Source:

Source Organism(s):

Homo sapiens (Taxon ID: 9606)

Expression System(s):

Escherichia coli bl21(de3)

Method Details:

Experimental Method:

X-RAY DIFFRACTION

Resolution:

2.80 Å

R-Value Free:

0.25

R-Value Work:

0.19

R-Value Observed:

0.19

Space Group:

P 61

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Macromolecular Entities

Structures with similar UniProt ID

Protein Blast

Polymer Type:polypeptide(L)
Molecule:Serine/threonine-protein kina
Gene (Uniprot):MARK2
Chain IDs:A, B
Chain Length:328
Number of Molecules:2
Biological Source:Homo sapiens

UniProt ID:Q7KZI7 Pfam ID:PF00069, PF00627

Ligand Molecules

24R

Primary Citation

Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties.

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.Show

Bioorg. Med. Chem. Lett. 26 4362 4366 (2016)

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

Abstact

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.

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Protein

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Disease

Primary Citation of related structures

Abstact

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