PDBsum entry 3ika

Transferase

PDB id: 3ika

Contents

Protein chain

310 a.a. *

Ligands

0UN

Waters ×148

* Residue conservation analysis

PDB id:

3ika

Name:

Transferase

Title:

Crystal structure of egfr 696-1022 t790m mutant covalently binding to wz4002

Structure:

Epidermal growth factor receptor. Chain: a, b. Fragment: 694-1022. Synonym: receptor tyrosine-protein kinase erbb-1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.90Å R-factor: 0.210 R-free: 0.257

Authors:

C.-H.Yun,M.J.Eck

Key ref:

W.Zhou et al. (2009). Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature, 462, 1070-1074. PubMed id: 20033049 DOI: 10.1038/nature08622

Date:

05-Aug-09 Release date: 12-Jan-10

Protein chains

P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor from Homo sapiens

Seq: 1210 a.a.

Struc: 310 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1038/nature08622

Nature 462:1070-1074 (2009)

PubMed id: 20033049

Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.

W.Zhou, D.Ercan, L.Chen, C.H.Yun, D.Li, M.Capelletti, A.B.Cortot, L.Chirieac, R.E.Iacob, R.Padera, J.R.Engen, K.K.Wong, M.J.Eck, N.S.Gray, P.A.Jänne.

ABSTRACT

The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.

Selected figure(s)

Figure 3.
Figure 3: Crystal structure of WZ4002 bound to EGFR T790M. a, Chemical structures of WZ8040 and WZ4002 are shown schematically in a manner resembling the conformation adopted in complex with the kinase. b, Crystal structure of WZ4002 in complex with EGFR T790M mutant (PDB ID 3IKA). WZ4002 binds the active conformation of the kinase, with both the regulatory C-helix and the ‘DFG’ segment of the activation loop in their inward, active positions. The EGFR kinase is shown in a ribbon representation (blue) with the bound inhibitor in yellow. Side-chain and main-chain atoms are shown for selected residues that contact the compound. Expected hydrogen bonds to the backbone amide and carbonyl atoms of Met 793 are indicated by dashed lines. Note also the covalent bond with Cys 797. The structure was refined to a crystallographic R value of 21.3% (R[free] = 25.4%) with data extending to 2.9-Å resolution (see Methods for further crystallographic details).

Figure 4.
Figure 4: WZ4002 inhibits EGFR phosphorylation and induces significant tumour regression in murine models of EGFR T790M. a, Two doses separated by 16 h of WZ4002 (2.5 mg kg^-1 or 25 mg kg^-1) or vehicle were administered to EGFR delE746_A750/T790M or L858R/T790M mice with MRI-confirmed tumours. The mice were killed, the lungs isolated, grossly dissected and subjected to cell lysis. Cell extracts were immunoblotted to detect the indicated proteins. b, Immunohistochemical analyses of tumours from EGFR delE746_A750/T790M mice from a using indicated antibodies. Scale bar, 50 μm. c, Quantification of TUNEL- and Ki67-positive cells from tumour nodules (n = 4) from vehicle- and WZ4002-treated mice. The means and standard deviations are plotted. *, P < 0.05. d, MRI images of vehicle- or WZ4002-treated mice at baseline (0 weeks: 0w) and after 2 weeks (2w) of treatment. e, Quantification of the relative tumour volume from MRI images from vehicle-treated mice (E746_A750/T790M (n = 3); L858R/T790M (n = 4)), and WZ4002-treated L858R/T790M (n = 3) and E746_A750/T790M (n = 3) mice. The means and standard deviations are plotted. f, Tumours from vehicle- and WZ4002-treated mice stained with haematoxylin and eosin. Low-power view (inset) demonstrates near-complete resolution of tumours in the WZ4002-treated mice. Scale bar, 100 μm.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2009, 462, 1070-1074) copyright 2009.

Figures were selected by an automated process.