4RJ5

EGFR kinase (T790M/L858R) with inhibitor compound 5

Summary for 4RJ5

• Entry DOI: 10.2210/pdb4rj5/pdb
• Related: 4RJ3 4RJ4 4RJ6 4RJ7 4RJ8
• Descriptor: Epidermal growth factor receptor, N-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]-2-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine (2 entities in total)
• Functional Keywords: protein kinase, phosphotransfer catalyst, 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: 37939.84

Authors

Eigenbrot, C.,Yu, C. (deposition date: 2014-10-08, release date: 2014-11-26, Last modification date: 2023-09-20)

Primary citation

Hanan, E.J.,Eigenbrot, C.,Bryan, M.C.,Burdick, D.J.,Chan, B.K.,Chen, Y.,Dotson, J.,Heald, R.A.,Jackson, P.S.,La, H.,Lainchbury, M.D.,Malek, S.,Purkey, H.E.,Schaefer, G.,Schmidt, S.,Seward, E.M.,Sideris, S.,Tam, C.,Wang, S.,Yeap, S.K.,Yen, I.,Yin, J.,Yu, C.,Zilberleyb, I.,Heffron, T.P.
Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation.
J.Med.Chem., 57:10176-10191, 2014

PubMed 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.

PubMed: 25383627
DOI: 10.1021/jm501578n

Experimental method

X-RAY DIFFRACTION (3.1 Å)