Developing Selective EphA2 Inhibitors for the treatment of Cancer

描述（由申请人提供）：针对特定驱动突变（如Bcr- Abl， EML4-ALK，突变EGFR和V600E b-raf）的蛋白激酶抑制剂具有显著的抗癌活性，正在彻底改变癌症药物的发现。越来越多的证据表明，EphA2激酶活性异常在许多类型的癌症中起着关键作用，包括乳腺癌、肺癌、卵巢癌、前列腺癌、胶质母细胞瘤和黑色素瘤，以及对各种受体酪氨酸激酶抑制剂的耐药性的一般机制。Eph系统是最大的酪氨酸激酶家族，有16个rtk和9个配体，涉及从早期发育过程中的模式形成到血管生成再到肿瘤发展过程中的去调控等一系列生物学功能。由于缺乏有效的、选择性的和特性良好的抑制剂，目前不可能对特定的Eph激酶的功能进行药理学研究。在这里，我们建议使用定向药物化学方法来开发EphA2的有效和选择性抑制剂，并使用这些化合物来验证EphA2作为黑色素瘤和肺癌的细胞和小鼠模型的潜在靶点。我们已经确定了I型和II型ATP竞争性抑制剂，例如9-14，它们对EphA2和其他Eph激酶表现出有效的活性，在这里，我们建议使用结构引导的药物化学进一步优化效力、选择性和药理学性质（目标1和2）。现有的和新生成的化合物将被广泛地描述其抗增殖活性，并与工程EphA2耐药等位基因结合，将用于验证EphA2作为黑色素瘤和肺癌的细胞和小鼠模型的潜在靶标（Aim 3）。我们的实验室在开发ALK、Mps1、Erk5、mTor、LRRK2、FGFRs、JNKs和EGFR的T790M突变形式的同类抑制剂方面取得了相当大的成功，并使用这些化合物来验证新的癌症靶点。为了实现这些目标，我们组建了一个世界级的多学科团队，整合了药物化学（Gray），结构生物学（Knapp）， EphA2信号传导（Chen），癌细胞生物学（Benes, Chen, Tsao），肿瘤模型（Wong, Chen）和临床护理（Tsao），这将使化学探针的开发能够检查EphA2激酶信号传导。

DESCRIPTION (provided by applicant): The dramatic anti-cancer activity of protein kinase inhibitors that target specific driver-mutations such as Bcr- Abl, EML4-ALK, mutant EGFR and V600E b-raf is revolutionizing cancer drug discovery. Emerging evidence suggests that abnormal EphA2 kinase activity plays a key role in many types of cancers, including breast, lung, ovary, prostate, glioblastoma, and melanoma as well as a general mechanism of drug resistance to inhibitors of various receptor tyrosine kinases. The Eph system is the largest tyrosine kinase family with 16 RTKs and 9 ligands and has been implicated in a vast array of biological functions ranging from pattern formation during early development to angiogenesis to de-regulation during tumor development. Pharmacological interrogation of the function of specific Eph kinases is currently impossible due to the lack of potent, selective and well- characterized inhibitors. Here we proposed to use a directed-medicinal chemistry approach to develop potent and selective inhibitors of EphA2 and to use these compounds to validate EphA2 as a potential target using cellular and murine models of melanoma and lung cancer. We have identified type I and type II ATP- competitive inhibitors exemplified by 9-14 that exhibit potent activity against EphA2 and other Eph kinases, and here we propose further optimization of potency, selectivity, and pharmacological properties using structure- guided medicinal chemistry (Aims 1&2). The existing and newly generated compounds will be broadly profiled for their antiproliferative activities and, in conjunction with engineered EphA2 drug-resistant alleles will be used to validate EphA2 as a potential target using cellular and murine models of melanoma and lung cancer (Aim 3). Our laboratory has had considerable success in developing first-in-class inhibitors of ALK, Mps1, Erk5, mTor, LRRK2, FGFRs, JNKs, and the T790M mutant form of EGFR and in using these compounds to validate new cancer targets. To accomplish these goals we have assembled a world-class, multidisciplinary team that integrates medicinal chemistry (Gray), structural biology (Knapp), Eph-signaling (Chen), cancer cell biology (Benes, Chen, Tsao), tumor models (Wong, Chen), and clinical care (Tsao) that will enable the development of chemical probes to interrogate EphA2 kinase signaling.