5HG9

EGFR (L858R, T790M, V948R) in complex with 1-[(3R,4R)-3-[({2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-(trifluoromethyl)pyrrolidin-1-yl]prop-2-en-1-one

Summary for 5HG9

• Entry DOI: 10.2210/pdb5hg9/pdb
• Related: 5HG5 5HG7 5HG8
• Descriptor: Epidermal growth factor receptor, 1-[(3R,4R)-3-[({2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-(trifluoromethyl)pyrrolidin-1-yl]propan-1-one, SULFATE ION, ... (5 entities in total)
• Functional Keywords: egfr, kinase, inhibitor, lung cancer, 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: 38486.28

Authors

Gajiwala, K.S. (deposition date: 2016-01-08, release date: 2016-02-03, Last modification date: 2016-03-23)

Primary citation

Cheng, H.,Nair, S.K.,Murray, B.W.,Almaden, C.,Bailey, S.,Baxi, S.,Behenna, D.,Cho-Schultz, S.,Dalvie, D.,Dinh, D.M.,Edwards, M.P.,Feng, J.L.,Ferre, R.A.,Gajiwala, K.S.,Hemkens, M.D.,Jackson-Fisher, A.,Jalaie, M.,Johnson, T.O.,Kania, R.S.,Kephart, S.,Lafontaine, J.,Lunney, B.,Liu, K.K.,Liu, Z.,Matthews, J.,Nagata, A.,Niessen, S.,Ornelas, M.A.,Orr, S.T.,Pairish, M.,Planken, S.,Ren, S.,Richter, D.,Ryan, K.,Sach, N.,Shen, H.,Smeal, T.,Solowiej, J.,Sutton, S.,Tran, K.,Tseng, E.,Vernier, W.,Walls, M.,Wang, S.,Weinrich, S.L.,Xin, S.,Xu, H.,Yin, M.J.,Zientek, M.,Zhou, R.,Kath, J.C.
Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants.
J.Med.Chem., 59:2005-2024, 2016

PubMed Abstract: First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.

PubMed: 26756222
DOI: 10.1021/acs.jmedchem.5b01633

Experimental method

X-RAY DIFFRACTION (2.15 Å)