3W2Q

EGFR kinase domain T790M/L858R mutant with HKI-272

Summary for 3W2Q

• Entry DOI: 10.2210/pdb3w2q/pdb
• Related: 2JIV 3POZ 3W2O 3W2P 3W2R 3W2S
• Descriptor: Epidermal growth factor receptor, N-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)butanamide, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (4 entities in total)
• Functional Keywords: anti-oncogene, cell cycle, disease mutation, kinase domain, receptor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38775.26

Authors

Sogabe, S.,Kawakita, Y.,Igaki, S. (deposition date: 2012-12-03, release date: 2013-01-16, Last modification date: 2023-11-08)

Primary citation

Sogabe, S.,Kawakita, Y.,Igaki, S.,Iwata, H.,Miki, H.,Cary, D.R.,Takagi, T.,Takagi, S.,Ohta, Y.,Ishikawa, T.
Structure-Based Approach for the Discovery of Pyrrolo[3,2-d]pyrimidine-Based EGFR T790M/L858R Mutant Inhibitors.
Acs Med.Chem.Lett., 4:201-205, 2013

PubMed Abstract: The epidermal growth factor receptor (EGFR) family plays a critical role in vital cellular processes and in various cancers. Known EGFR inhibitors exhibit distinct antitumor responses against the various EGFR mutants associated with nonsmall-cell lung cancer. The L858R mutation enhances clinical sensitivity to gefitinib and erlotinib as compared with wild type and reduces the relative sensitivity to lapatinib. In contrast, the T790M mutation confers drug resistance to gefitinib and erlotinib. We determined crystal structures of the wild-type and T790M/L858R double mutant EGFR kinases with reversible and irreversible pyrrolo[3,2-d]pyrimidine inhibitors based on analogues of TAK-285 and neratinib. In these structures, M790 adopts distinct conformations to accommodate different inhibitors, whereas R858 allows conformational variations of the activation loop. These results provide structural insights for understanding the structure-activity relationships that should contribute to the development of potent inhibitors against drug-sensitive or -resistant EGFR mutations.

PubMed: 24900643
DOI: 10.1021/ml300327z

Experimental method

X-RAY DIFFRACTION (2.2 Å)