3W32

EGFR kinase domain complexed with compound 20a

Summary for 3W32

• Entry DOI: 10.2210/pdb3w32/pdb
• Related: 3POZ 3W33
• Descriptor: Epidermal growth factor receptor, 4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-N-[2-(methylsulfonyl)ethyl]-8,9-dihydro-7H-pyrimido[4,5-b]azepine-6-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: anti-oncogene, cell cycle, disease mutation, kinase domain, receptor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• Total number of polymer chains: 1
• Total formula weight: 38241.51

Authors

Sogabe, S.,Kawakita, Y. (deposition date: 2012-12-07, release date: 2013-03-06, Last modification date: 2023-11-08)

Primary citation

Kawakita, Y.,Seto, M.,Ohashi, T.,Tamura, T.,Yusa, T.,Miki, H.,Iwata, H.,Kamiguchi, H.,Tanaka, T.,Sogabe, S.,Ohta, Y.,Ishikawa, T.
Design and synthesis of novel pyrimido[4,5-b]azepine derivatives as HER2/EGFR dual inhibitors
Bioorg.Med.Chem., 21:2250-2261, 2013

PubMed 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.

PubMed: 23490150
DOI: 10.1016/j.bmc.2013.02.014

Experimental method

X-RAY DIFFRACTION (1.8 Å)