Discovery and optimization of novel mutant-selective allosteric inhibitors of EGFR T790M

摘要： 表皮生长因子受体（EGFR）酪氨酸激酶结构域的体细胞突变是一种新的免疫抑制剂。 肺腺癌的常见病因。尽管EGFR突变型肺癌的靶向治疗取得了显著进展， 在癌症中，治疗获得性耐药性仍然是一个主要问题。 了解和克服对EGFR酪氨酸激酶抑制剂（TKI）和 其它靶向疗法是癌症医学的中心问题。我们的长期目标是开发更有效的 以及对EGFR突变型肺癌的耐受性更好的疗法，产生持久的反应。我们认为 同时使用多种靶向突变型EGFR的药物治疗可预防耐药性的出现 突变，导致更持久的反应。然而，具有替代的抗肿瘤机制的合适的化合物也是可能的。 以前没有采取过行动。与绝大多数TKI一样，目前所有EGFR TKI均靶向ATP- 激酶的位置。我们的多学科研究团队在EGFR突变型肺癌方面拥有深厚的专业知识， 成功发现抑制剂的记录。在最初的资助期，我们开发了高效的变构抑制剂， 基于苯甘氨酸支架，其作为单一药剂有效对抗L 858 R/T790 M， L 858 R/T790 M/C797 S EGFR变体在体外和人非小细胞肺癌小鼠模型中的表达。的 这些变构抑制剂的不同作用机制和结合位点，以及它们缺乏对 WT EGFR和其他蛋白激酶的结合使其作为联合治疗的候选者特别有吸引力。 在这次更新中，我们将发现靶向ATP和变构位点的化合物是否真的可以 协同作用以提供前所未有的疗效、耐受性和反应的持久性。我们通过以下方式实现这一目标： 具体目标如下：目标1，我们将开发第二个化学系列的高效，多选择性 基于苯并二氮杂卓酮骨架的变构EGFR抑制剂。目标2，我们将设计和优化 同时结合突变EGFR的相邻ATP和变构位点的互补抑制剂对 具有高度的积极合作性。据我们所知，高度合作的多位点抑制 以前在治疗开发的背景下进行了探索。目标3，我们将进行临床前确认 变构EGFR抑制剂和互补的ATP位点/变构对，包括测试它们的体内功效 在EGFR突变肺癌的异种移植模型中， 双重目标这些目标的成功实现将为新的治疗方法提供概念验证 EGFR突变型肺癌

Abstract: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are a common cause of lung adenocarcinoma. Despite marked advances in targeted therapies for EGFR-mutant lung cancer, treatment-acquired resistance remains a major problem. Understanding and overcoming acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) and to other targeted therapies is a central problem in cancer medicine. Our long term goal is to develop more effective and better tolerated therapies for EGFR mutant lung cancer that yield durable responses. We reason that simultaneous treatment with multiple agents targeting mutant EGFR may prevent emergence of resistance mutations, leading to more durable responses. However, suitable compounds with alternative mechanisms of action have not previously been available. Like the vast majority of TKIs, all current EGFR TKIs target the ATP- site of the kinase. Our multidisciplinary research team has deep expertise in EGFR-mutant lung cancer and a record of successful inhibitor discovery. In the initial grant period, we developed highly potent allosteric inhibitors based on a phenylglycine scaffold that are effective as single agents against L858R/T790M and L858R/T790M/C797S EGFR variants in vitro and in mouse models of human non-small cell lung cancer. The distinct mechanism of action and binding site of these allosteric inhibitors, together with their lack of potency on WT EGFR and other protein kinases, makes them especially attractive as candidates for combination therapy. In this renewal, we will discover whether compounds that target the ATP and allosteric sites can indeed synergize to deliver unprecedented efficacy, tolerability and durability of responses. We pursue this goal through the following specific aims: Aim 1, We will develop a second chemical series of highly potent, mutant-selective allosteric EGFR inhibitors based on a benzodiazepinone scaffold. Aim 2, We will design and optimize complementary pairs of inhibitors that simultaneously bind the adjacent ATP and allosteric sites of mutant EGFR with a high degree of positive cooperativity. To our knowledge, highly cooperative, multi-site inhibition has not been previously explored in the context of therapeutic development. Aim 3, We will perform pre-clinical validation of allosteric EGFR inhibitors and complementary ATP-site/allosteric pairs, including testing their in vivo efficacy in xenograft models of EGFR mutant lung cancer and assessing the potential for resistance to arise in the context of dual targeting. Successful execution of these aims will provide proof of concept for a new therapeutic approach in EGFR mutant lung cancer.