7BJX

Crystal structure of CHK1-10pt-mutant complex with compound 26


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.204 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

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This is version 1.3 of the entry. See complete history


Literature

Design and Synthesis of Pyrrolo[2,3- d ]pyrimidine-Derived Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Checkpoint Kinase 1 (CHK1)-Derived Crystallographic Surrogate.

Williamson, D.S.Smith, G.P.Mikkelsen, G.K.Jensen, T.Acheson-Dossang, P.Badolo, L.Bedford, S.T.Chell, V.Chen, I.J.Dokurno, P.Hentzer, M.Newland, S.Ray, S.C.Shaw, T.Surgenor, A.E.Terry, L.Wang, Y.Christensen, K.V.

(2021) J Med Chem 64: 10312-10332

  • DOI: https://doi.org/10.1021/acs.jmedchem.1c00720
  • Primary Citation of Related Structures:  
    7BJD, 7BJE, 7BJH, 7BJJ, 7BJM, 7BJO, 7BJR, 7BJX, 7BK1, 7BK2, 7BK3, 7BKN, 7BKO

  • PubMed Abstract: 

    Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3- d ]pyrimidines underwent optimization using X-ray structures of LRRK2 kinase domain surrogates, based on checkpoint kinase 1 (CHK1) and a CHK1 10-point mutant. (2 R )-2-Methylpyrrolidin-1-yl derivative 18 (LRRK2 G2019S c K i 0.7 nM, LE 0.66) was identified, with increased potency consistent with an X-ray structure of 18 /CHK1 10-pt. mutant showing the 2-methyl substituent proximal to Ala147 (Ala2016 in LRRK2). Further structure-guided elaboration of 18 gave the 2-[(1,3-dimethyl-1 H -pyrazol-4-yl)amino] derivative 32 . Optimization of 32 afforded diastereomeric oxolan-3-yl derivatives 44 and 45 , which demonstrated a favorable in vitro PK profile, although they displayed species disconnects in the in vivo PK profile, and a propensity for P-gp- and/or BCRP-mediated efflux in a mouse model. Compounds 44 and 45 demonstrated high potency and exquisite selectivity for LRRK2 and utility as chemical probes for the study of LRRK2 inhibition.


  • Organizational Affiliation

    Vernalis (R&D) Ltd., Granta Park, Great Abington, Cambridge CB21 6GB, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase Chk1
A, B
297Homo sapiensMutation(s): 10 
Gene Names: CHEK1CHK1
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O14757 (Homo sapiens)
Explore O14757 
Go to UniProtKB:  O14757
PHAROS:  O14757
GTEx:  ENSG00000149554 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO14757
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
U0Q (Subject of Investigation/LOI)
Query on U0Q

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
4-amino-7-methyl-2-[(1-methyl-1H-pyrazol-4-yl)amino]-6-[(2R)-2-methylpyrrolidin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile
C17 H21 N9
QQIQPTYOVZSTDB-SNVBAGLBSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.204 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.993α = 90
b = 65.942β = 101.32
c = 110.057γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted U0QClick on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2021-07-07
    Type: Initial release
  • Version 1.1: 2021-07-21
    Changes: Derived calculations
  • Version 1.2: 2021-08-04
    Changes: Database references
  • Version 1.3: 2024-01-31
    Changes: Data collection, Database references, Refinement description