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

项目概要 胰腺导管腺癌 (PDAC) 是一种致命且常见的胰腺癌，具有以下特点： 存活率极低。由于缺乏明显的早期症状，大多数患者表现为 诊断时患有转移性 PDAC。转移性 PDAC 的有效治疗方法有限，并且 手术是唯一的治疗方法，美国最近因以下原因死亡的人数不断增加 PDAC。基质金属蛋白酶-2 (MMP-2)，一种与发育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，MMP-2 抑制剂在临床试验中失败，很大程度上是由于疗效低、毒性高。我们建议重点关注 MMP-2 上游的酶将有助于开发更有效的 PDAC 疗法。探测 MEK4（也称为 MAP2K4）就是这样一种酶，它将对其在增殖中的作用提供重要的见解。 转移性 PDAC。已观察到 MEK4 表达增加会增加 PDAC 的转移 在多项体外和体内研究中。不幸的是，目前不存在 MEK4 的化学探针。杠杆作用 我们发布的用于询问 MEK 激酶家族抑制剂选择性的平台，以及我们发布的 致力于开发 MEK4 的初步先导药物，该提案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、体外的培训平台 生物测定、X 射线晶体学、分子生物学和癌症模型，本文中描述的研究 该提案旨在为 MEK4 在调节转移中的作用提供新的见解。与我的赞助商合作， Scheidt 教授将提供化学合成方面的强化培训，而我的共同赞助者 Munshi 教授将提供 癌症生物学及其相关技术方面的类似综合培训。这项研究将进行 作为西北大学化学系和 范伯格医学院（血液学和肿瘤学以及卢里癌症中心），并得到以下机构的进一步支持 外部合作者。通过这种协作努力，我将发展知识和技能，以有效和 有效地设计连接化学和生物学的实验。最终，这些研究将调查疗效 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.