4OTF

Crystal structure of the kinase domain of Bruton's Tyrosine kinase with GDC0834


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.167 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Potent and selective Bruton's tyrosine kinase inhibitors: Discovery of GDC-0834.

Young, W.B.Barbosa, J.Blomgren, P.Bremer, M.C.Crawford, J.J.Dambach, D.Gallion, S.Hymowitz, S.G.Kropf, J.E.Lee, S.H.Liu, L.Lubach, J.W.Macaluso, J.Maciejewski, P.Maurer, B.Mitchell, S.A.Ortwine, D.F.Di Paolo, J.Reif, K.Scheerens, H.Schmitt, A.Sowell, C.G.Wang, X.Wong, H.Xiong, J.M.Xu, J.Zhao, Z.Currie, K.S.

(2015) Bioorg Med Chem Lett 25: 1333-1337

  • DOI: https://doi.org/10.1016/j.bmcl.2015.01.032
  • Primary Citation of Related Structures:  
    4OTF

  • PubMed Abstract: 

    SAR studies focused on improving the pharmacokinetic (PK) properties of the previously reported potent and selective Btk inhibitor CGI-1746 (1) resulted in the clinical candidate GDC-0834 (2), which retained the potency and selectivity of CGI-1746, but with much improved PK in preclinical animal models. Structure based design efforts drove this work as modifications to 1 were investigated at both the solvent exposed region as well as 'H3 binding pocket'. However, in vitro metabolic evaluation of 2 revealed a non CYP-mediated metabolic process that was more prevalent in human than preclinical species (mouse, rat, dog, cyno), leading to a high-level of uncertainly in predicting human pharmacokinetics. Due to its promising potency, selectivity, and preclinical efficacy, a single dose IND was filed and 2 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, 2 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure. This information informed the back-up program and discovery of improved inhibitors.


  • Organizational Affiliation

    Genentech, 1 DNA Way, South San Francisco, CA 94080, 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: AGMX1ATKBPKBTK
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
2VL
Query on 2VL

Download Ideal Coordinates CCD File 
E [auth A]N-{3-[6-({4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl }-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide
C33 H36 N6 O3 S
CDOOFZZILLRUQH-GDLZYMKVSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A],
D [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
OCS
Query on OCS
A
L-PEPTIDE LINKINGC3 H7 N O5 SCYS
Binding Affinity Annotations 
IDSourceBinding Affinity
2VL BindingDB:  4OTF IC50: min: 2.3, max: 60 (nM) from 4 assay(s)
EC50: min: 350, max: 380 (nM) from 2 assay(s)
Binding MOAD:  4OTF IC50: 6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.167 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 108.507α = 90
b = 108.507β = 90
c = 42.221γ = 120
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-01-28
    Type: Initial release
  • Version 1.1: 2015-04-01
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary
  • Version 1.3: 2023-12-06
    Changes: Data collection