3THB

Structure of PLK1 kinase domain in complex with a benzolactam-derived inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.250 
  • R-Value Observed: 0.253 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of a Potent and Orally Bioavailable Benzolactam-Derived Inhibitor of Polo-Like Kinase 1 (MLN0905).

Duffey, M.O.Vos, T.J.Adams, R.Alley, J.Anthony, J.Barrett, C.Bharathan, I.Bowman, D.Bump, N.J.Chau, R.Cullis, C.Driscoll, D.L.Elder, A.Forsyth, N.Frazer, J.Guo, J.Guo, L.Hyer, M.L.Janowick, D.Kulkarni, B.Lai, S.J.Lasky, K.Li, G.Li, J.Liao, D.Little, J.Peng, B.Qian, M.G.Reynolds, D.J.Rezaei, M.Scott, M.P.Sells, T.B.Shinde, V.Shi, Q.J.Sintchak, M.D.Soucy, F.Sprott, K.T.Stroud, S.G.Nestor, M.Visiers, I.Weatherhead, G.Ye, Y.D'Amore, N.

(2012) J Med Chem 55: 197-208

  • DOI: https://doi.org/10.1021/jm2011172
  • Primary Citation of Related Structures:  
    3THB

  • PubMed Abstract: 

    This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.


  • Organizational Affiliation

    Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, United States. matthew.duffey@mpi.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase PLK1333Homo sapiensMutation(s): 1 
Gene Names: PLK1PLK
EC: 2.7.11.21
UniProt & NIH Common Fund Data Resources
Find proteins for P53350 (Homo sapiens)
Explore P53350 
Go to UniProtKB:  P53350
PHAROS:  P53350
GTEx:  ENSG00000166851 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP53350
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3TA
Query on 3TA

Download Ideal Coordinates CCD File 
C [auth A]9-chloro-2-({5-[3-(dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-thi one
C23 H25 Cl N6 S
MYVQSDVXBZNNLF-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3TA Binding MOAD:  3THB IC50: 2 (nM) from 1 assay(s)
PDBBind:  3THB IC50: 2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.250 
  • R-Value Observed: 0.253 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.668α = 90
b = 67.668β = 90
c = 154.684γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-11-23
    Type: Initial release
  • Version 1.1: 2012-01-25
    Changes: Database references
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary