PDBsum entry 3w33

Transferase/transferase inhibitor

PDB id: 3w33

Contents

Protein chain

297 a.a.

Ligands

W19

SO4

Waters ×127

PDB id:

3w33

Name:

Transferase/transferase inhibitor

Title:

Egfr kinase domain complexed with compound 19b

Structure:

Epidermal growth factor receptor. Chain: a. 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. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

1.70Å R-factor: 0.199 R-free: 0.233

Authors:

S.Sogabe,Y.Kawakita

Key ref:

Y.Kawakita et al. (2013). Design and synthesis of novel pyrimido[4,5-b]azepine derivatives as HER2/EGFR dual inhibitors. Bioorg Med Chem Lett, 21, 2250-2261. PubMed id: 23490150 DOI: 10.1016/j.bmc.2013.02.014

Date:

07-Dec-12 Release date: 06-Mar-13

Protein chain

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

Seq: 1210 a.a.

Struc: 297 a.a.

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: 10.1016/j.bmc.2013.02.014

Bioorg Med Chem Lett 21:2250-2261 (2013)

PubMed id: 23490150

Design and synthesis of novel pyrimido[4,5-b]azepine derivatives as HER2/EGFR dual inhibitors.

Y.Kawakita, M.Seto, T.Ohashi, T.Tamura, T.Yusa, H.Miki, H.Iwata, H.Kamiguchi, T.Tanaka, S.Sogabe, Y.Ohta, T.Ishikawa.

ABSTRACT

A novel 7,6 fused bicyclic scaffold, pyrimido[4,5-b]azepine was designed to fit into the ATP binding site of the HER2/EGFR proteins. The synthesis of this scaffold was accomplished by an intramolecular Claisen-type condensation. As the results of optimization lead us to 4-anilino and 6-functional groups, we discovered 6-substituted amide derivative 19b, which has a 1-benzothiophen-4-yloxy group attached to the 4-anilino group. An X-ray co-crystal structure of 19b with EGFR demonstrated that the N-1 and N-3 nitrogens of the pyrimido[4,5-b]azepine scaffold make hydrogen-bonding interactions with the main chain NH of Met793 and the side chain of Thr854 via a water-mediated hydrogen bond network, respectively. In addition, the NH proton at the 9-position makes an additional hydrogen bond with the carbonyl group of Met793, as we expected. Compound 19b revealed potent HER2/EGFR kinase (IC50: 24/36 nM) and BT474 cell growth (GI50: 18 nM) inhibitory activities based on its pseudo-irreversible (PI) profile.