4RJ5: Egfr Kinase (t790m/l858r) With Inhibitor Compound 5

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.
PDB ID: 4RJ5Download
MMDB ID: 125081
PDB Deposition Date: 2014/10/8
Updated in MMDB: 2014/12
Experimental Method:
x-ray diffraction
Resolution: 3.1  Å
Source Organism:
Similar Structures:
Biological Unit for 4RJ5: monomeric; determined by author and by software (PISA)
Molecular Components in 4RJ5
Label Count Molecule
Protein (1 molecule)
Epidermal Growth Factor Receptor(Gene symbol: EGFR)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB