6O8I

BTK In Complex With Inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.42 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.195 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton's Tyrosine Kinase (BTK).

Watterson, S.H.Liu, Q.Beaudoin Bertrand, M.Batt, D.G.Li, L.Pattoli, M.A.Skala, S.Cheng, L.Obermeier, M.T.Moore, R.Yang, Z.Vickery, R.Elzinga, P.A.Discenza, L.D'Arienzo, C.Gillooly, K.M.Taylor, T.L.Pulicicchio, C.Zhang, Y.Heimrich, E.McIntyre, K.W.Ruan, Q.Westhouse, R.A.Catlett, I.M.Zheng, N.Chaudhry, C.Dai, J.Galella, M.A.Tebben, A.J.Pokross, M.Li, J.Zhao, R.Smith, D.Rampulla, R.Allentoff, A.Wallace, M.A.Mathur, A.Salter-Cid, L.Macor, J.E.Carter, P.H.Fura, A.Burke, J.R.Tino, J.A.

(2019) J Med Chem 62: 3228-3250

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b00167
  • Primary Citation of Related Structures:  
    6O8I

  • PubMed Abstract: 

    Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.


  • Organizational Affiliation

    Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543 , United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase BTK269Homo sapiensMutation(s): 0 
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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LTJ (Subject of Investigation/LOI)
Query on LTJ

Download Ideal Coordinates CCD File 
B [auth A]4-[(3S)-3-{[(2E)-but-2-enoyl]amino}piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide
C20 H25 F N4 O2
BCSXUDNOTSZTNK-BPJJOFIESA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.42 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.195 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.131α = 90
b = 105.334β = 90
c = 38.052γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-04-03
    Type: Initial release
  • Version 1.1: 2019-04-24
    Changes: Data collection, Database references