Synthesis, and Evaluation of Potent and Selective MEK4 Inhibitors as a Targeted Therapeutic for Metastatic Pancreatic Ductal Adenocarcinoma

项目摘要 摘要胰腺导管腺癌(PDAC)是一种常见的致命性胰腺癌。 存活率极低。由于缺乏明显的早期症状，大多数患者出现 诊断时有转移性动脉导管未闭。转移性PDAC的有效治疗方法有限，以及 手术是唯一的治愈方法，美国最近看到越来越多的人死于 PDAC。基质金属蛋白酶-2(MMP2)是一种与肿瘤发生发展直接相关的金属蛋白酶 转移性癌症作为阻止转移的治疗靶点，已被广泛研究。然而，基质金属蛋白酶-2 抑制剂在临床试验中失败了，很大程度上是由于疗效低和毒性高。我们建议把重点放在 基质金属蛋白酶-2上游的酶将允许开发更有效的治疗PDAC的方法。探查 其中一种名为MEK4(也称为MAP2K4)的酶将使人们对其在增殖中的作用有重要的了解 转移性动脉导管未闭。已经观察到MEK4的表达增加会增加PDAC的转移 在多个体外和体内研究中。不幸的是，目前还不存在针对MEK4的化学探针。利用 我们已公布的跨MEK激酶家族的抑制剂选择性测试平台，以及我们已公布的 在为MEK4制定初步领导的工作中，这项提议的重点是填补这一空白。作为一个多学科 利用合成有机化学、计算建模、药物化学、体外培训平台 生物分析、X射线结晶学、分子生物学和癌症模型，其中描述的研究 该提案旨在为MEK4在调节转移中的作用提供新的见解。和我的赞助人一起工作， Scheidt教授将提供化学合成方面的强化培训，而我的共同赞助人Munshi教授将提供 同样，在癌症生物学及其相关技术方面的全面培训。这项研究将继续进行 作为西北大学化学系和 范伯格医学院(血液学和肿瘤学和卢里癌症中心)，并得到 外部通敌者。通过这种合作努力，我将发展知识和技能，以高效和 有效地设计连接化学和生物的实验。最终，这些研究将调查其疗效。 MEK4抑制剂作为PDAC的靶向治疗。

Project Summary Pancreatic ductal adenocarcinoma (PDAC) is a deadly and common form of pancreatic cancer with an extremely low rate of survival. Due to the lack of distinct early-stage symptoms, most patients present with metastatic PDAC at the time of diagnosis. With limited effective treatments available for metastatic PDAC, and surgery being the only curative treatment, the US has recently seen an increasing number of fatalities due to PDAC. Matrix metalloproteinase-2 (MMP-2), a metalloproteinase directly associated with the development of metastatic cancers, has been heavily studied as a therapeutic target for stopping metastasis. However, MMP-2 inhibitors have failed in clinical trials, largely due to low efficacy and high toxicity. We propose that a focus on enzymes upstream from MMP-2 will allow for the development of more effective therapies for PDAC. Probing one such enzyme, MEK4 (otherwise known as MAP2K4), would give crucial insight into its role in proliferating metastatic PDAC. Increased expression of MEK4 has already been observed to increase metastasis in PDAC in multiple in vitro and in vivo studies. Unfortunately, no chemical probes for MEK4 currently exist. Leveraging our published platform for interrogating inhibitor selectivity across the MEK kinase family, as well as our published work on developing an initial lead for MEK4, this proposal is focused on filling this gap. As a multidisciplinary training platform utilizing synthetic organic chemistry, computational modeling, medicinal chemistry, in vitro biological assays, X-ray crystallography, molecular biology, and cancer models, the studies described in this proposal aim to provide new insights into the roles of MEK4 in regulating metastasis. Working with my sponsor, Prof. Scheidt, will provide intensive training in chemical synthesis, while my co-sponsor, Prof. Munshi, will provide similarly comprehensive training in cancer biology and its associated techniques. This research will be carried out as part of a collaborative effort between the Northwestern University Department of Chemistry and the Feinberg School of Medicine (Hematology and Oncology and Lurie Cancer Center), with further support from outside collaborators. Through this collaborative effort, I will develop the knowledge and skills to efficiently and effectively design experiments that bridge chemistry and biology. Ultimately, these studies will survey the efficacy of MEK4 inhibitors as targeted therapies for PDAC.