5HG8

EGFR (L858R, T790M, V948R) in complex with N-[3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)phenyl]prop-2-enamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.42 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.208 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants.

Cheng, H.Nair, S.K.Murray, B.W.Almaden, C.Bailey, S.Baxi, S.Behenna, D.Cho-Schultz, S.Dalvie, D.Dinh, D.M.Edwards, M.P.Feng, J.L.Ferre, R.A.Gajiwala, K.S.Hemkens, M.D.Jackson-Fisher, A.Jalaie, M.Johnson, T.O.Kania, R.S.Kephart, S.Lafontaine, J.Lunney, B.Liu, K.K.Liu, Z.Matthews, J.Nagata, A.Niessen, S.Ornelas, M.A.Orr, S.T.Pairish, M.Planken, S.Ren, S.Richter, D.Ryan, K.Sach, N.Shen, H.Smeal, T.Solowiej, J.Sutton, S.Tran, K.Tseng, E.Vernier, W.Walls, M.Wang, S.Weinrich, S.L.Xin, S.Xu, H.Yin, M.J.Zientek, M.Zhou, R.Kath, J.C.

(2016) J Med Chem 59: 2005-2024

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01633
  • Primary Citation of Related Structures:  
    5HG5, 5HG7, 5HG8, 5HG9

  • PubMed Abstract: 

    First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.


  • Organizational Affiliation

    La Jolla Laboratories, Pfizer Worldwide Research and Development , 10770 Science Center Drive, San Diego, California 92121, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Epidermal growth factor receptor329Homo sapiensMutation(s): 3 
Gene Names: EGFRERBBERBB1HER1
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00533 (Homo sapiens)
Explore P00533 
Go to UniProtKB:  P00533
PHAROS:  P00533
GTEx:  ENSG00000146648 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00533
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.42 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.208 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.932α = 90
b = 69.73β = 90
c = 110.61γ = 90
Software Package:
Software NamePurpose
CNXrefinement
SCALAdata scaling
autoPROCdata 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: 2016-02-03
    Type: Initial release
  • Version 1.1: 2016-02-10
    Changes: Database references
  • Version 1.2: 2016-03-23
    Changes: Database references
  • Version 1.3: 2017-11-22
    Changes: Database references, Derived calculations, Refinement description
  • Version 1.4: 2024-03-06
    Changes: Data collection, Database references, Refinement description