3RCD

HER2 Kinase Domain Complexed with TAK-285

Summary for 3RCD

• Entry DOI: 10.2210/pdb3rcd/pdb
• Related: 3POZ 3PP0
• Descriptor: Receptor tyrosine-protein kinase erbB-2, N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide (3 entities in total)
• Functional Keywords: kinase domain, receptor, transferase, tyrosine-protein kinase, tyrosine kinase inhibitor, transferase-transferase inhibitor complex, anti-oncogene, cell cycle, disease, mutation, atp-binding, nucleotide-binding, glycoprotein, phosphoprotein, membrane, secreted, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Cytoplasm. Isoform 3: Cytoplasm: P04626
• Total number of polymer chains: 4
• Total formula weight: 154011.96

Authors

Aertgeerts, K.,Skene, R.,Sogabe, S. (deposition date: 2011-03-30, release date: 2011-11-23, Last modification date: 2023-09-13)

Primary citation

Ishikawa, T.,Seto, M.,Banno, H.,Kawakita, Y.,Oorui, M.,Taniguchi, T.,Ohta, Y.,Tamura, T.,Nakayama, A.,Miki, H.,Kamiguchi, H.,Tanaka, T.,Habuka, N.,Sogabe, S.,Yano, J.,Aertgeerts, K.,Kamiyama, K.
Design and Synthesis of Novel Human Epidermal Growth Factor Receptor 2 (HER2)/Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors Bearing a Pyrrolo[3,2-d]pyrimidine Scaffold.
J.Med.Chem., 54:8030-8050, 2011

PubMed Abstract: Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors' ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.

PubMed: 22003817
DOI: 10.1021/jm2008634

Experimental method

X-RAY DIFFRACTION (3.21 Å)