3O50

Crystal structure of benzamide 9 bound to AuroraA


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.351 
  • R-Value Work: 0.285 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine aurora kinase inhibitor.

Cee, V.J.Schenkel, L.B.Hodous, B.L.Deak, H.L.Nguyen, H.N.Olivieri, P.R.Romero, K.Bak, A.Be, X.Bellon, S.Bush, T.L.Cheng, A.C.Chung, G.Coats, S.Eden, P.M.Hanestad, K.Gallant, P.L.Gu, Y.Huang, X.Kendall, R.L.Lin, M.H.Morrison, M.J.Patel, V.F.Radinsky, R.Rose, P.E.Ross, S.Sun, J.R.Tang, J.Zhao, H.Payton, M.Geuns-Meyer, S.D.

(2010) J Med Chem 53: 6368-6377

  • DOI: https://doi.org/10.1021/jm100394y
  • Primary Citation of Related Structures:  
    3O50, 3O51

  • PubMed Abstract: 

    The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142 and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. vcee@amgen.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cDNA FLJ58295, highly similar to Serine/threonine-protein kinase 6
A, B
267Homo sapiensMutation(s): 0 
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O14965 (Homo sapiens)
Explore O14965 
Go to UniProtKB:  O14965
PHAROS:  O14965
GTEx:  ENSG00000087586 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO14965
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LJE
Query on LJE

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
N-{3-methyl-4-[(3-pyrimidin-4-ylpyridin-2-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide
C24 H17 F3 N4 O2
OHDDQNLJTAKXQT-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.351 
  • R-Value Work: 0.285 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 118.32α = 90
b = 125β = 90
c = 76.11γ = 90
Software Package:
Software NamePurpose
AMoREphasing
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2010-08-18 
  • Deposition Author(s): Huang, X.

Revision History  (Full details and data files)

  • Version 1.0: 2010-08-18
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2024-02-21
    Changes: Data collection, Database references, Derived calculations