RRC ID 65019
著者 Cheng H, Nair SK, Murray BW, Almaden C, Bailey S, Baxi S, Behenna D, Cho-Schultz S, Dalvie D, Dinh DM, Edwards MP, Feng JL, Ferre RA, Gajiwala KS, Hemkens MD, Jackson-Fisher A, Jalaie M, Johnson TO, Kania RS, Kephart S, Lafontaine J, Lunney B, Liu KK, Liu Z, Matthews J, Nagata A, Niessen S, Ornelas MA, Orr ST, 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 SL, Xin S, Xu H, Yin MJ, Zientek M, Zhou R, Kath JC.
タイトル 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.
ジャーナル J Med Chem
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.
巻・号 59(5)
ページ 2005-24
公開日 2016-3-10
DOI 10.1021/acs.jmedchem.5b01633
PMID 26756222
MeSH Carcinoma, Non-Small-Cell Lung / drug therapy Carcinoma, Non-Small-Cell Lung / genetics Dose-Response Relationship, Drug Drug Discovery* ErbB Receptors / antagonists & inhibitors* ErbB Receptors / genetics* Humans Lung Neoplasms / drug therapy Lung Neoplasms / genetics Models, Molecular Molecular Structure Mutant Proteins / antagonists & inhibitors* Mutation Protein Kinase Inhibitors / chemical synthesis Protein Kinase Inhibitors / chemistry Protein Kinase Inhibitors / pharmacology* Pyrimidines / chemical synthesis Pyrimidines / chemistry Pyrimidines / pharmacology* Pyrroles / chemical synthesis Pyrroles / chemistry Pyrroles / pharmacology* Structure-Activity Relationship Tumor Cells, Cultured
IF 6.205
リソース情報
ヒト・動物細胞 PC-9(RCB4455)