4RJ3

CDK2 with EGFR inhibitor compound 8


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.63 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.177 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation.

Hanan, E.J.Eigenbrot, C.Bryan, M.C.Burdick, D.J.Chan, B.K.Chen, Y.Dotson, J.Heald, R.A.Jackson, P.S.La, H.Lainchbury, M.D.Malek, S.Purkey, H.E.Schaefer, G.Schmidt, S.Seward, E.M.Sideris, S.Tam, C.Wang, S.Yeap, S.K.Yen, I.Yin, J.Yu, C.Zilberleyb, I.Heffron, T.P.

(2014) J Med Chem 57: 10176-10191

  • DOI: https://doi.org/10.1021/jm501578n
  • Primary Citation of Related Structures:  
    4RJ3, 4RJ4, 4RJ5, 4RJ6, 4RJ7, 4RJ8

  • PubMed Abstract: 

    Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. We describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.


  • Organizational Affiliation

    Departments of †Discovery Chemistry, ‡Structural Biology, §Drug Metabolism and Pharmacokinetics, ∥Biochemical and Cellular Pharmacology, ⊥Molecular Oncology, and #Protein Expression, Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cyclin-dependent kinase 2298Homo sapiensMutation(s): 0 
Gene Names: CDK2CDKN2
EC: 2.7.11.22
UniProt & NIH Common Fund Data Resources
Find proteins for P24941 (Homo sapiens)
Explore P24941 
Go to UniProtKB:  P24941
PHAROS:  P24941
GTEx:  ENSG00000123374 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP24941
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3QS
Query on 3QS

Download Ideal Coordinates CCD File 
C [auth A]1-cyclopentyl-N-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]-1H-pyrrolo[3,2-c]pyridin-6-amine
C22 H28 N6 O
BYMFSZLMPVZBJV-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
B [auth A]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
ALY
Query on ALY
A
L-PEPTIDE LINKINGC8 H16 N2 O3LYS
Binding Affinity Annotations 
IDSourceBinding Affinity
3QS Binding MOAD:  4RJ3 IC50: 93 (nM) from 1 assay(s)
BindingDB:  4RJ3 IC50: 93 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.63 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.177 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.102α = 90
b = 70.923β = 90
c = 72.586γ = 90
Software Package:
Software NamePurpose
B3data collection
PHASERphasing
REFMACrefinement
HKL-2000data 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: 2014-11-26
    Type: Initial release
  • Version 1.1: 2014-12-10
    Changes: Database references
  • Version 1.2: 2015-01-14
    Changes: Database references