Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study
Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study
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DOI：
10.1021/acs.jmedchem.5b01412
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发表时间：
2015-11-26
影响因子：
7.3
通讯作者：
Heffron, Timothy P.
中科院分区：
文献类型：
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作者：
Heald, Robert;Bowman, Krista K.;Heffron, Timothy P.
由于其对激活突变体的活性增加，第一代表皮生长因子受体（EGFR）激酶抑制剂在治疗非小细胞肺癌（NSCLC）患者方面取得了显着的成功，但通过看门人残基的二次突变获得的耐药性意味着临床反应仅持续8-14个月。解决这一未满足的医疗需求需要能够靶向两种最常见的双突变体的药物：T790 M/L 858 R（TMLR）和T790 M/del（746-750）（TMdel）。在此，我们描述了如何使用专注于结构引导的效力增加而不增加亲脂性或减少三维特征的策略来优化非共价双突变体选择性先导化合物。在连续几轮的设计和合成之后，发现在4-羟基-和4-甲氧基哌啶基上的顺式-氟取代提供了协同的，实质性的，和通过与酶的直接相互作用和/或对邻近配体氧原子的作用获得的特异性效力。氟羟基哌啶系列的进一步开发导致鉴定出一对非对映体，其显示50-在体外对T790 M突变体的基于酶和细胞的选择性超过野生型EGFR（wtEGFR）的倍数，以及在体内异种移植模型中的途径敲低。
Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom Further development of the flurohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.