PDBsum entry 4g5p

Transferase/transferase inhibitor

PDB id: 4g5p

Contents

Protein chains

299 a.a.

Ligands

0WN

Waters ×38

PDB id:

4g5p

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of egfr kinase t790m in complex with bibw2992

Structure:

Epidermal growth factor receptor. Chain: a, b. Fragment: kinase domain, unp residues 696-1022. Synonym: proto-oncogenE C-erbb-1, receptor tyrosine-protein kinase erbb-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606

Resolution:

3.17Å R-factor: 0.247 R-free: 0.323

Authors:

F.Solca,G.Dahl,A.Zoephel,G.Bader,M.Sanderson,C.Klein,O.Kraemer, F.Himmelsbach,E.Haaksma,G.R.Adolf

Key ref:

F.Solca et al. (2012). Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther, 343, 342-350. PubMed id: 22888144

Date:

18-Jul-12 Release date: 29-Aug-12

Protein chains

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

Seq: 1210 a.a.

Struc: 299 a.a.*

* PDB and UniProt seqs differ at 9 residue positions (black crosses)

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

J Pharmacol Exp Ther 343:342-350 (2012)

PubMed id: 22888144

Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker.

F.Solca, G.Dahl, A.Zoephel, G.Bader, M.Sanderson, C.Klein, O.Kraemer, F.Himmelsbach, E.Haaksma, G.R.Adolf.

ABSTRACT

Deregulation of the ErbB (proto-oncogene B of the avian erythroblastosis virus AEV-H strain) receptor network is well recognized as an oncogenic driver in epithelial cancers. Several targeted drugs have been developed, including antibodies and small-molecule kinase inhibitors, each of them characterized by distinct patterns of ErbB receptor interactions. Understanding the precise pharmacological properties of these compounds is important for optimal use in clinical practice. Afatinib [BIBW 2992; N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide] is an ATP-competitive anilinoquinazoline derivative harboring a reactive acrylamide group. It was designed to covalently bind and irreversibly block enzymatically active ErbB receptor family members. Here, we show by X-ray crystallography the covalent binding of afatinib to wild-type epidermal growth factor receptor (EGFR) and by mass spectrometry the covalent interaction with EGFR, EGFR(L858R/T790M), human epidermal growth factor receptor 2 (HER2), and ErbB-4. Afatinib potently inhibits the enymatic activity of ErbB-4 (EC(50) = 1 nM) and the proliferation of cancer cell lines driven by multiple ErbB receptor aberrations at concentrations below 100 nM. N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butanamide (BI 37781), a close analog of afatinib lacking the acrylamide group and thus incapable of covalent bond formation, had similar potency on cells driven by EGFR or EGFR(L858R), but less or no detectable activity on cells expressing EGFR(L858R/ T790M) HER2 or ErbB-4. These results stress the importance of the acrylamide group and show that afatinib differs from approved ErbB targeting agents by irreversibly inhibiting the kinase activity of all ErbB family members. They provide a mechanistic rationale for the distinct pharmacological features of this compound and explain the clinical activity seen in some patients who are resistant to antibody or kinase inhibitor therapy because of secondary mutations or ErbB receptor "reprogramming."