Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor
Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor
复制标题
DOI：
10.1021/jm500973a
复制
发表时间：
2014-10-23
影响因子：
7.3
通讯作者：
Wrigley, Gail L.
中科院分区：
文献类型：
--
作者：
Finlay, M. Raymond V.;Anderton, Mark;Wrigley, Gail L.
多年来，表皮生长因子受体（EGFR）抑制剂已在临床上用于治疗携带致敏（或激活）突变的非小细胞肺癌（NSCLC）患者。尽管这些药物的临床疗效令人鼓舞，但在许多患者中，耐药性的发展导致疾病进展。在大多数情况下，这种耐药性是以T790 M突变的形式出现的。此外，这些药物固有的EGFR野生型受体抑制可导致皮疹和腹泻的剂量限制性毒性。我们在本文中描述了早期突变选择性导致临床候选物AZD 9291的演变，AZD 9291是EGFR敏化（EGFRm+）和T790 M抗性突变的不可逆抑制剂，其选择性超过受体的野生型形式。在临床前模型中观察到显著的肿瘤抑制作用后，临床候选药物在临床上用于T790 M阳性EGFR-TKI耐药NSCLC患者，观察到早期疗效，并伴有令人鼓舞的安全性特征
Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile