PDBsum entry 5edp

Transferase/transferase inhibitor

PDB id: 5edp

Contents

Protein chain

295 a.a.

PDB id:

5edp

Name:

Transferase/transferase inhibitor

Title:

Egfr kinase (t790m/l858r) apo

Structure:

Epidermal growth factor receptor. Chain: a. Synonym: proto-oncogenE C-erbb-1,receptor tyrosine-protein kinase erbb-1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.90Å R-factor: 0.202 R-free: 0.244

Authors:

C.Eigenbrot,C.Yu

Key ref:

E.J.Hanan et al. (2016). 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. PubMed id: 26639762 DOI: 10.1016/j.bmcl.2015.11.078

Date:

21-Oct-15 Release date: 02-Dec-15

Protein chain

P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor from Homo sapiens

Seq: 1210 a.a.

Struc: 295 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.bmcl.2015.11.078

Bioorg Med Chem Lett 26:534-539 (2016)

PubMed id: 26639762

4-Aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of mutant epidermal growth factor receptor tyrosine kinase.

E.J.Hanan, M.Baumgardner, M.C.Bryan, Y.Chen, C.Eigenbrot, P.Fan, X.H.Gu, H.La, S.Malek, H.E.Purkey, G.Schaefer, S.Schmidt, S.Sideris, I.Yen, C.Yu, T.P.Heffron.

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.