5EAK

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.198 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

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.

(2016) Bioorg Med Chem Lett 26: 4362-4366

  • DOI: https://doi.org/10.1016/j.bmcl.2016.02.003
  • Primary Citation of Related Structures:  
    5EAK

  • 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.


  • Organizational Affiliation

    Discovery Chemistry, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase MARK2
A, B
328Homo sapiensMutation(s): 0 
Gene Names: MARK2EMK1
EC: 2.7.11.1 (PDB Primary Data), 2.7.11.26 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for Q7KZI7 (Homo sapiens)
Explore Q7KZI7 
Go to UniProtKB:  Q7KZI7
PHAROS:  Q7KZI7
GTEx:  ENSG00000072518 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ7KZI7
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
24R
Query on 24R

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
N-[(1S,2R)-2-aminocyclohexyl]-4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide
C21 H23 N7 O S
LYADGAGFYYXXIO-MSOLQXFVSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.198 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 118.739α = 90
b = 118.739β = 90
c = 106.592γ = 120
Software Package:
Software NamePurpose
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing
PHENIXrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2016-02-17 
  • Deposition Author(s): Su, H.P.

Revision History  (Full details and data files)

  • Version 1.0: 2016-02-17
    Type: Initial release
  • Version 1.1: 2016-08-24
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Database references, Derived calculations, Refinement description
  • Version 1.3: 2024-03-06
    Changes: Data collection, Database references