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
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
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DOI：
10.1021/acs.jmedchem.5b01633
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发表时间：
2016-03-10
影响因子：
7.3
通讯作者：
Kath, John C.
中科院分区：
文献类型：
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作者：
Cheng, Hengmiao;Nair, Sajiv K.;Kath, John C.
第一代EGFR TKI（吉非替尼、厄洛替尼）为EGFR致癌突变的NSCLC癌症患者提供了显著的临床获益。最终，这些患者的疾病进展，通常由EGFR激酶结构域（T790 M）中的第二位点突变驱动。第一代药物的另一个不利因素是WT EGFR抑制导致的严重不良事件。因此，我们的目标是开发一种高效的不可逆抑制剂，在耐药双突变体（L 858 R/T790 M，Del/T790 M）和WT EGFR之间具有最大的选择性比。开发共价抑制剂的独特方法，可逆结合亲和力的优化，是这项工作的基石。PF-06459988被发现是一种新型的第三代不可逆抑制剂，对含T790 M的双突变EGFR表现出高效力和特异性，（ii）亲电子弹头的固有化学反应性最低，（iii）相对于早期不可逆EGFR抑制剂，蛋白质组反应性大大降低，（iv）对WT EGFR的活性最低
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 (0 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