The design, synthesis, and characterization of potent and selective MEK7 inhibitors as targeted therapies for T-cell acute lymphoblastic leukemia

作为 T 细胞急性淋巴细胞白血病靶向治疗的有效选择性 MEK7 抑制剂的设计、合成和表征

• 批准号: 10358492
• 负责人: Dalton Robert Kim
• 金额: $ 5.01万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2023-03-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358492
• 关键词: Acute Lymphocytic Leukemia; Acute T Cell Leukemia; Age; Binding; Biological; Biological Assay; Cancer Etiology; Cell Line; Cell model; Cessation of life; Chemicals; Chemoresistance; Childhood Acute Lymphocytic Leukemia; Covalent Interaction; Cysteine; DNA Double Strand Break; DNA Repair; Development; Discipline; Disease Resistance; Disease remission; Exhibits; Extracellular Signal Regulated Kinases; Family; Functional disorder; GKLF protein; Genes; Genetic Transcription; Genome Stability; Glutathione; Hematologic Neoplasms; Hematology; In Vitro; Investigation; Kinetics; Lead; MAP3K1 gene; MAPK8 gene; MEKKs; MEKs; Malignant Childhood Neoplasm; Mass Spectrum Analysis; Mediator of activation protein; Methodology; Methods; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Modality; Modeling; Molecular; Molecular Biology; Mutation; N-terminal; Nature; Oncogenes; Organic Synthesis; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiological; Process; Protein Biochemistry; Protein Isoforms; Proteins; Protocols documentation; Publishing; Regulation; Repression; Resistance; Roentgen Rays; Role; Signal Pathway; Signal Transduction; Signaling Protein; Specificity; Surveys; Tumor Suppressor Proteins; Validation; Zinc Fingers; activity-based protein profiling; arm; base; chemotherapy; clinically significant; comparative; computational chemistry; cytotoxicity; design; experimental study; human disease; improved; in vivo; inhibitor; insight; leukemia; mortality; mouse model; mutant; novel; patient derived xenograft model; pediatric patients; protein expression; rational design; small molecule; small molecule inhibitor; targeted treatment; therapy resistant; tool; transcription factor; treatment strategy

Project Summary Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in pediatric patients and the most frequent cause of cancer-related mortality before the age of 20. Current treatment strategies act by non-specific mechanisms that are incapable of achieving and maintaining remission in the nearly 1 out of 4 pediatric patients with therapy-resistant disease. While targeted therapies are not currently available for ALL patients, they could potentially improve patient outcomes by interfering with pathological cellular and molecular activities that facilitate resistance to multi-agent chemotherapy. Increased expression of protein kinase MEK7 and consequent amplification of downstream MAP kinase signaling have been identified as two such processes facilitating chemoresistance in T-cell ALL (T-ALL), rendering MEK7 an attractive target for T-ALL directed therapies. Unfortunately, there are no small molecules known to potently and selectively inhibit this MEK isoform. Leveraging our published platform for interrogating inhibitor selectivity across the MEK kinase family, we have designed and synthesized a lead compound exhibiting potent MEK7 inhibition. The objective of my present proposal is the further development and optimization of a potent and selective small molecule MEK7 inhibitor to chemically probe aberrant signaling in this arm of the MAPK pathway in T-ALL models. Our methodology entails a multifaceted approach employing strategies from disciplines spanning computational chemistry, organic synthesis, protein biochemistry, and molecular biology. Through these complementary modalities, we seek to gain new insight into the roles of the least understood MEK isoform in the molecular pathophysiology underlying T-ALL. Of utmost clinical significance, the studies in this proposal will survey the efficacy of direct MEK7 inhibitors as targeted therapies for T-ALL.

项目概要 急性淋巴细胞白血病（ALL）是儿科患者中最常见的血液恶性肿瘤， 20 岁之前癌症相关死亡的最常见原因。目前的治疗策略是 近四分之一的人无法实现和维持缓解的非特异性机制 患有耐药性疾病的儿科患者。虽然靶向治疗目前不适用于所有疾病 患者，他们可以通过干扰病理细胞和分子来潜在地改善患者的治疗结果 促进对多药化疗耐药的活动。蛋白激酶 MEK7 表达增加 下游 MAP 激酶信号传导的后续放大已被确定为两个这样的过程 促进 T 细胞 ALL (T-ALL) 的化学耐药性，使 MEK7 成为 T-ALL 定向的有吸引力的靶标 疗法。不幸的是，目前还没有已知的小分子能够有效且选择性地抑制这种 MEK 同工型。利用我们发布的平台来询问 MEK 激酶家族的抑制剂选择性， 我们设计并合成了一种具有有效 MEK7 抑制作用的先导化合物。我的目标 目前的建议是进一步开发和优化有效的选择性小分子 MEK7 抑制剂，用于化学探测 T-ALL 模型中 MAPK 通路臂中的异常信号传导。我们的 方法论需要采用多方面的方法，采用跨计算学科的策略 化学、有机合成、蛋白质生物化学和分子生物学。通过这些互补 模态，我们寻求对最不了解的 MEK 异构体在分子生物学中的作用获得新的见解。 T-ALL 的病理生理学基础。最具临床意义的是，本提案中的研究将调查 直接 MEK7 抑制剂作为 T-ALL 靶向治疗的疗效。