Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR,Journal of Medicinal Chemistry

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Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-03-29 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01894
Simon Planken , Douglas C. Behenna , Sajiv K. Nair , Theodore O. Johnson , Asako Nagata , Chau Almaden , Simon Bailey , T. Eric Ballard , Louise Bernier , Hengmiao Cheng , Sujin Cho-Schultz , Deepak Dalvie , Judith G. Deal , Dac M. Dinh , Martin P. Edwards , Rose Ann Ferre , Ketan S. Gajiwala , Michelle Hemkens , Robert S. Kania , John C. Kath , Jean Matthews , Brion W. Murray , Sherry Niessen , Suvi T. M. Orr , Mason Pairish , Neal W. Sach , Hong Shen , Manli Shi , James Solowiej , Khanh Tran , Elaine Tseng , Paolo Vicini , Yuli Wang , Scott L. Weinrich , Ru Zhou , Michael Zientek , Longqing Liu ₁ , Yiqin Luo ₁ , Shuibo Xin ₁ , Chengyi Zhang ₁ , Jennifer Lafontaine

Affiliation

Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.

中文翻译：

的发现ñ - （（3 - [R，4 - [R）-4-氟-1-（6 - （（3-甲氧基-1-甲基-1- ħ吡唑-4-基）氨基）-9-甲基-9- ħ -嘌呤-2-基）吡咯烷-3-基）丙烯酰胺（PF-06747775）通过基于结构的药物设计：一种针对野生型EGFR选择性靶向致癌EGFR突变体的高亲和力不可逆抑制剂

突变表皮生长因子受体（EGFR）是非小细胞肺癌（NSCLC）的主要驱动力。在耐药机制使这些抑制剂无效之前，市售的第一代抑制剂（例如埃洛替尼）会对EGFR突变型NSCLC患者产生短暂的有益应答。继发性致癌EGFR突变约占复发的50％，最常见的是Gatekeeper T790M替代，这使现有疗法无效。最近披露了发现EGFR T790M突变体不可逆的吡咯并嘧啶抑制剂PF-06459988（1）的发现。1本文中，我们描述了我们为实现跨越EGFR致癌突变的效力和改善的基因组选择性所做的持续努力，从而发现了临床候选药物PF-06747775（21），可提供针对四种常见突变体（外显子19缺失（Del），L858R和双重突变体T790M / L858R和T790M / Del）的有效EGFR活性，对野生型EGFR的选择性以及理想的ADME特性。目前正在突变EGFR驱动的NSCLC的I期临床试验中对化合物21进行评估。

更新日期：2017-03-29

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