3ORN

Mitogen-activated protein kinase kinase 1 (MEK1) in complex with CH4987655 and MgAMP-PNP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.234 
  • R-Value Observed: 0.236 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent.

Isshiki, Y.Kohchi, Y.Iikura, H.Matsubara, Y.Asoh, K.Murata, T.Kohchi, M.Mizuguchi, E.Tsujii, S.Hattori, K.Miura, T.Yoshimura, Y.Aida, S.Miwa, M.Saitoh, R.Murao, N.Okabe, H.Belunis, C.Janson, C.Lukacs, C.Schuck, V.Shimma, N.

(2011) Bioorg Med Chem Lett 21: 1795-1801

  • DOI: https://doi.org/10.1016/j.bmcl.2011.01.062
  • Primary Citation of Related Structures:  
    3ORN, 3OS3

  • PubMed Abstract: 

    The MAP kinase pathway is one of the most important pathways involved in cell proliferation and differentiation, and its components are promising targets for antitumor drugs. Design and synthesis of a novel MEK inhibitor, based on the 3D-structural information of the target enzyme, and then multidimensional optimization including metabolic stability, physicochemical properties and safety profiles were effectively performed and led to the identification of a clinical candidate for an orally available potent MEK inhibitor, CH4987655, possessing a unique 3-oxo-oxazinane ring structure at the 5-position of the benzamide core structure. CH4987655 exhibits slow dissociation from the MEK enzyme, remarkable in vivo antitumor efficacy both in mono- and combination therapy, desirable metabolic stability, and insignificant MEK inhibition in mouse brain, implying few CNS-related side effects in human. An excellent PK profile and clear target inhibition in PBMC were demonstrated in a healthy volunteer clinical study.


  • Organizational Affiliation

    Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd, Kamakura, Kanagawa, Japan. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dual specificity mitogen-activated protein kinase kinase 1307Homo sapiensMutation(s): 0 
Gene Names: MAP2K1MEK1PRKMK1
EC: 2.7.12.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q02750 (Homo sapiens)
Explore Q02750 
Go to UniProtKB:  Q02750
PHAROS:  Q02750
GTEx:  ENSG00000169032 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ02750
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3OR
Query on 3OR

Download Ideal Coordinates CCD File 
D [auth A]3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-1,2-oxazinan-2-yl)methyl]benzamide
C20 H19 F3 I N3 O5
FIMYFEGKMOCQKT-UHFFFAOYSA-N
ANP
Query on ANP

Download Ideal Coordinates CCD File 
B [auth A]PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
C10 H17 N6 O12 P3
PVKSNHVPLWYQGJ-KQYNXXCUSA-N
PGE
Query on PGE

Download Ideal Coordinates CCD File 
E [auth A]TRIETHYLENE GLYCOL
C6 H14 O4
ZIBGPFATKBEMQZ-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
F [auth A]
G [auth A]
H [auth A]
I [auth A]
J [auth A]
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
MG
Query on MG

Download Ideal Coordinates CCD File 
C [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3OR BindingDB:  3ORN Kd: min: 0.24, max: 8.7 (nM) from 2 assay(s)
IC50: 8.8 (nM) from 1 assay(s)
PDBBind:  3ORN Kd: 0.24 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.234 
  • R-Value Observed: 0.236 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 136.67α = 90
b = 136.67β = 90
c = 60.906γ = 120
Software Package:
Software NamePurpose
CNXrefinement
DENZOdata reduction
SCALAdata scaling
CNXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-03-02
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-08-23
    Changes: Data collection, Refinement description, Source and taxonomy
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations