6MX8

Crystal structure of anaplastic lymphoma kinase (ALK) bound by Brigatinib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.

Huang, W.S.Liu, S.Zou, D.Thomas, M.Wang, Y.Zhou, T.Romero, J.Kohlmann, A.Li, F.Qi, J.Cai, L.Dwight, T.A.Xu, Y.Xu, R.Dodd, R.Toms, A.Parillon, L.Lu, X.Anjum, R.Zhang, S.Wang, F.Keats, J.Wardwell, S.D.Ning, Y.Xu, Q.Moran, L.E.Mohemmad, Q.K.Jang, H.G.Clackson, T.Narasimhan, N.I.Rivera, V.M.Zhu, X.Dalgarno, D.Shakespeare, W.C.

(2016) J Med Chem 59: 4948-4964

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00306
  • Primary Citation of Related Structures:  
    6MX8

  • PubMed Abstract: 

    In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.


  • Organizational Affiliation

    ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ALK tyrosine kinase receptor307Homo sapiensMutation(s): 0 
Gene Names: ALK
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UM73 (Homo sapiens)
Explore Q9UM73 
Go to UniProtKB:  Q9UM73
PHAROS:  Q9UM73
GTEx:  ENSG00000171094 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9UM73
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6GY
Query on 6GY

Download Ideal Coordinates CCD File 
B [auth A]5-chloro-N~4~-[2-(dimethylphosphoryl)phenyl]-N~2~-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine
C29 H39 Cl N7 O2 P
AILRADAXUVEEIR-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6GY BindingDB:  6MX8 IC50: min: 0.37, max: 4.9 (nM) from 3 assay(s)
Binding MOAD:  6MX8 IC50: 0.37 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.891α = 90
b = 57.502β = 90
c = 103.986γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-12-12
    Type: Initial release
  • Version 1.1: 2024-03-13
    Changes: Data collection, Database references