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

强效选择性 MEK4 抑制剂作为转移性胰腺导管腺癌靶向治疗的合成和评估

• 批准号: 10223882
• 负责人: Ada Jade Kwong
• 金额: $ 3.63万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-07-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223882
• 关键词: Apoptosis; Biological; Biological Assay; Biology; Cancer Biology; Cancer Center; Cancer Etiology; Cancer Model; Cell Line; Cell physiology; Cells; Cessation of life; Chemicals; Chemistry; Clinical; Clinical Trials; Computer Models; Development; Diagnosis; Differentiation and Growth; Disease; Disseminated Malignant Neoplasm; Enzymes; Evaluation; Exhibits; Family; Future; Gelatinase A; Goals; Hematology; In Vitro; Investigation; Knowledge; Lead; Libraries; MAP2K1 gene; MAP3K1 gene; MAPK8 gene; MEKs; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediator of activation protein; Metalloproteases; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Biology; Mus; Mutate; Neoplasm Metastasis; Oncology; Operative Surgical Procedures; Organic Chemistry; Organoids; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Chemistry; Phosphotransferases; Proliferating; Protein Isoforms; Protocols documentation; Publishing; Research; Research Training; Role; Signal Transduction; Signaling Protein; Stimulus; Structure; Surveys; Survival Rate; Symptoms; Techniques; Thalidomide; Therapeutic; Time; Toxic effect; Training; United States; Universities; Work; X-Ray Crystallography; analog; arm; base; cell growth; chemical synthesis; comparative; curative treatments; cytotoxicity; design; driving force; effective therapy; experimental study; extracellular; in silico; in vitro testing; in vivo; in vivo Model; inhibitor/antagonist; innovation; insight; lead optimization; malignant breast neoplasm; medical schools; meetings; mortality; multidisciplinary; novel; novel strategies; overexpression; p38 Mitogen Activated Protein Kinase; pancreatic ductal adenocarcinoma cell; prevent; senescence; skills; small molecule; small molecule inhibitor; targeted treatment; therapeutic target; therapeutically effective; tumor progression; upstream kinase

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.

项目总结