論文 - 詳細
| 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 17 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 3.0 |
| リソース情報 | |
| ヒト・動物細胞 | PC-9(RCB4455) |