6OMU

Structure of human Bruton's Tyrosine Kinase in complex with Evobrutinib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.41 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 

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This is version 1.2 of the entry. See complete history


Literature

Discovery of Evobrutinib: An Oral, Potent, and Highly Selective, Covalent Bruton's Tyrosine Kinase (BTK) Inhibitor for the Treatment of Immunological Diseases.

Caldwell, R.D.Qiu, H.Askew, B.C.Bender, A.T.Brugger, N.Camps, M.Dhanabal, M.Dutt, V.Eichhorn, T.Gardberg, A.S.Goutopoulos, A.Grenningloh, R.Head, J.Healey, B.Hodous, B.L.Huck, B.R.Johnson, T.L.Jones, C.Jones, R.C.Mochalkin, I.Morandi, F.Nguyen, N.Meyring, M.Potnick, J.R.Santos, D.C.Schmidt, R.Sherer, B.Shutes, A.Urbahns, K.Follis, A.V.Wegener, A.A.Zimmerli, S.C.Liu-Bujalski, L.

(2019) J Med Chem 62: 7643-7655

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b00794
  • Primary Citation of Related Structures:  
    6OMU

  • PubMed Abstract: 

    Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity), which preclude their evaluation in nononcology indications. Here, we report the discovery and preclinical characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclinical pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clinical investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.


  • Organizational Affiliation

    EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase BTK271Homo sapiensMutation(s): 0 
Gene Names: BTKAGMX1ATKBPK
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q06187 (Homo sapiens)
Explore Q06187 
Go to UniProtKB:  Q06187
PHAROS:  Q06187
GTEx:  ENSG00000010671 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ06187
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MZJ
Query on MZJ

Download Ideal Coordinates CCD File 
C [auth A]1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one
C25 H27 N5 O2
QUIWHXQETADMGN-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
B [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
MZJ Binding MOAD:  6OMU IC50: 8.9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.41 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.173α = 90
b = 104.52β = 90
c = 37.983γ = 90
Software Package:
Software NamePurpose
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-08-14
    Type: Initial release
  • Version 1.1: 2019-09-25
    Changes: Data collection, Database references
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Refinement description