5EDR

EGFR kinase (T790M/L858R) with inhibitor compound 27: ~{N}-(1~{H}-indazol-3-yl)-7,7-dimethyl-2-(2-methylpyrazol-3-yl)-5~{H}-furo[3,4-d]pyrimidin-4-amine

Summary for 5EDR

• Entry DOI: 10.2210/pdb5edr/pdb
• Related: 5EDP 5EDQ
• Descriptor: Epidermal growth factor receptor, ~{N}-(1~{H}-indazol-3-yl)-7,7-dimethyl-2-(2-methylpyrazol-3-yl)-5~{H}-furo[3,4-d]pyrimidin-4-amine (3 entities in total)
• Functional Keywords: protein kinase, inhibitor, 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: 37910.80

Authors

Eigenbrot, C.,Yu, C. (deposition date: 2015-10-21, release date: 2015-12-02, Last modification date: 2024-03-06)

Primary citation

Hanan, E.J.,Baumgardner, M.,Bryan, M.C.,Chen, Y.,Eigenbrot, C.,Fan, P.,Gu, X.H.,La, H.,Malek, S.,Purkey, H.E.,Schaefer, G.,Schmidt, S.,Sideris, S.,Yen, I.,Yu, C.,Heffron, T.P.
4-Aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of mutant epidermal growth factor receptor tyrosine kinase.
Bioorg.Med.Chem.Lett., 26:534-539, 2016

PubMed Abstract: The treatment of epidermal growth factor receptor (EGFR)-driven non-small cell lung cancers with the T790M resistance mutation remains a significant unmet medical need. We report the identification of 4-aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of EGFR, with excellent activity against the T790M resistance double mutants and initial single activating mutants. Using an optimization strategy focused on structure-based design and improving PK properties through metabolite identification, we obtained advanced leads with high oral exposure.

PubMed: 26639762
DOI: 10.1016/j.bmcl.2015.11.078

Experimental method

X-RAY DIFFRACTION (2.6 Å)