5GMP

Crystal structure of EGFR 696-1022 T790M in complex with XTF-262

Summary for 5GMP

• Entry DOI: 10.2210/pdb5gmp/pdb
• Descriptor: Epidermal growth factor receptor, N-[3-[2-[[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino]-5-methyl-7-oxidanylidene-pyrido[2,3-d]pyrimidin-8-yl]phenyl]prop-2-enamide (3 entities in total)
• Functional Keywords: egfr, t790m, xtf-262, inhibitor, transferase
• 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: 38176.20

Authors

Yan, X.E.,Yun, C.H. (deposition date: 2016-07-14, release date: 2017-06-28, Last modification date: 2024-10-16)

Primary citation

Yu, L.,Huang, M.,Xu, T.,Tong, L.,Yan, X.E.,Zhang, Z.,Xu, Y.,Yun, C.,Xie, H.,Ding, K.,Lu, X.
A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFR(L858R/T790M) mutant with improved pharmacokinetic properties.
Eur J Med Chem, 126:1107-1117, 2017

PubMed Abstract: Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFR inhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFR kinase and inhibited the proliferation of H1975 cells with IC values of 2.0 nM and 40 nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERK in NCIH1975 cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.

PubMed: 28033579
DOI: 10.1016/j.ejmech.2016.12.006

Experimental method

X-RAY DIFFRACTION (2.797 Å)