4W8E

Structure of MST3 with a pyrrolopyrimidine inhibitor (PF-06645342)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor.

Henderson, J.L.Kormos, B.L.Hayward, M.M.Coffman, K.J.Jasti, J.Kurumbail, R.G.Wager, T.T.Verhoest, P.R.Noell, G.S.Chen, Y.Needle, E.Berger, Z.Steyn, S.J.Houle, C.Hirst, W.D.Galatsis, P.

(2015) J Med Chem 58: 419-432

  • DOI: https://doi.org/10.1021/jm5014055
  • Primary Citation of Related Structures:  
    4U8Z, 4W8D, 4W8E

  • PubMed Abstract: 

    Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies.


  • Organizational Affiliation

    Worldwide Medicinal Chemistry, ‡Neuroscience Research Unit, and §Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase 24 36 kDa subunit291Homo sapiensMutation(s): 0 
Gene Names: STK24MST3STK3
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y6E0 (Homo sapiens)
Explore Q9Y6E0 
Go to UniProtKB:  Q9Y6E0
PHAROS:  Q9Y6E0
GTEx:  ENSG00000102572 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y6E0
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3JB
Query on 3JB

Download Ideal Coordinates CCD File 
B [auth A]3-{4-[(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzonitrile
C20 H17 N7 O2
SAOVTENLRUIQAM-MRXNPFEDSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TPO
Query on TPO
A
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
3JB BindingDB:  4W8E IC50: 9430 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 47.53α = 90
b = 56.49β = 111.41
c = 61.06γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-03-18
    Type: Initial release
  • Version 1.1: 2023-12-27
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description, Source and taxonomy
  • Version 1.2: 2024-11-20
    Changes: Structure summary