5JEB

Crystal structure of EGFR tyrosine kinase domain with novel inhibitor of active state of HER2

Summary for 5JEB

• Entry DOI: 10.2210/pdb5jeb/pdb
• Descriptor: Epidermal growth factor receptor, SULFATE ION, 3-(furan-2-yl)-N-[5-(furan-2-yl)-2-methoxyphenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3 entities in total)
• Functional Keywords: inhibitor, kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 39122.07

Authors

Park, J.H.,Lemmon, M.A. (deposition date: 2016-04-18, release date: 2016-09-07, Last modification date: 2023-09-27)

Primary citation

Novotny, C.J.,Pollari, S.,Park, J.H.,Lemmon, M.A.,Shen, W.,Shokat, K.M.
Overcoming resistance to HER2 inhibitors through state-specific kinase binding.
Nat.Chem.Biol., 12:923-930, 2016

PubMed Abstract: The heterodimeric receptor tyrosine kinase complex formed by HER2 and HER3 can act as an oncogenic driver and is also responsible for rescuing a large number of cancers from a diverse set of targeted therapies. Inhibitors of these proteins, particularly HER2, have dramatically improved patient outcomes in the clinic, but recent studies have demonstrated that stimulating the heterodimeric complex, either via growth factors or by increasing the concentrations of HER2 and HER3 at the membrane, significantly diminishes the activity of the inhibitors. To identify an inhibitor of the active HER2-HER3 oncogenic complex, we developed a panel of Ba/F3 cell lines suitable for ultra-high-throughput screening. Medicinal chemistry on the hit scaffold resulted in a previously uncharacterized inhibitor that acts through preferential inhibition of the active state of HER2 and, as a result, is able to overcome cellular mechanisms of resistance such as growth factors or mutations that stabilize the active form of HER2.

PubMed: 27595329
DOI: 10.1038/nchembio.2171

Experimental method

X-RAY DIFFRACTION (3.298 Å)