PDBsum entry 4rj7

Transferase/transferase inhibitor

PDB id: 4rj7

Contents

Protein chain

295 a.a.

Ligands

SO4

3R1

Waters ×28

PDB id:

4rj7

Name:

Transferase/transferase inhibitor

Title:

Egfr kinase (t790m/l858r) with inhibitor compound 1

Structure:

Epidermal growth factor receptor. Chain: a. Fragment: kinase domain (unp residues 695-1022). 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:

2.55Å R-factor: 0.207 R-free: 0.234

Authors:

C.Eigenbrot,C.Yu

Key ref:

E.J.Hanan et al. (2014). Discovery of selective and noncovalent diaminopyrimidine-based inhibitors of epidermal growth factor receptor containing the T790M resistance mutation. J Med Chem, 57, 10176-10191. PubMed id: 25383627 DOI: 10.1021/jm501578n

Date:

08-Oct-14 Release date: 26-Nov-14

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: 10.1021/jm501578n

J Med Chem 57:10176-10191 (2014)

PubMed id: 25383627

Discovery of selective and noncovalent diaminopyrimidine-based inhibitors of epidermal growth factor receptor containing the T790M resistance mutation.

E.J.Hanan, C.Eigenbrot, M.C.Bryan, D.J.Burdick, B.K.Chan, Y.Chen, J.Dotson, R.A.Heald, P.S.Jackson, H.La, M.D.Lainchbury, S.Malek, H.E.Purkey, G.Schaefer, S.Schmidt, E.M.Seward, S.Sideris, C.Tam, S.Wang, S.K.Yeap, I.Yen, J.Yin, C.Yu, I.Zilberleyb, T.P.Heffron.

ABSTRACT

Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. We describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.