Developing Selective EphA2 Inhibitors for the treatment of Cancer

描述(由申请人提供)：针对BCR-Abl、EML4-ALK、突变的EGFR和V600E b-RAF等特定驱动突变的蛋白激酶抑制剂具有戏剧性的抗癌活性，正在彻底改变癌症药物的发现。新的证据表明，EphA2激酶活性异常在乳腺癌、肺癌、卵巢癌、前列腺癌、胶质母细胞瘤和黑色素瘤等多种癌症中起关键作用，也是多种受体酪氨酸激酶抑制剂耐药的一般机制。Eph系统是最大的酪氨酸激酶家族，有16个RTK和9个配体，参与了广泛的生物学功能，从早期发育的模式形成到肿瘤发展过程中的血管生成和去调节。由于缺乏有效的、选择性的和特征明确的抑制剂，目前还不可能对特定的Eph激酶的功能进行药理学询问。在这里，我们建议使用定向药物化学方法来开发有效和选择性的EphA2抑制剂，并使用这些化合物来验证EphA2作为潜在靶点的细胞和小鼠黑色素瘤和肺癌模型。我们已经确定了以9-14为代表的I型和II型ATP竞争性抑制剂，它们对EphA2和其他EphK表现出强大的活性，在这里，我们建议使用结构导向药物化学(目标1和2)进一步优化效力、选择性和药理性质。现有的和新生成的化合物将广泛用于它们的抗增殖活性，并将与改造的EphA2抗药等位基因一起用于验证EphA2作为潜在靶点的细胞和小鼠黑色素瘤和肺癌模型(AIM 3)。我们的实验室在开发ALK、Mps1、ERK5、mTOR、LRRK2、FGFRs、JNKs和EGFR的T790M突变形式的一流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，我们组建了一支世界级的多学科团队，该团队集成了药物化学(Gray)、结构生物学(Knapp)、Eph信号转导(Chen)、癌细胞生物学(Benes、Chen、Tsao)、肿瘤模型(Wong、Chen)和临床护理(Tsao)，将使开发能够询问EphA2激酶信号的化学探针成为可能。

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.