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.

项目摘要 急性淋巴细胞白血病（ALL）是儿科患者最常见的血液恶性肿瘤， 是20岁之前癌症相关死亡的最常见原因。目前的治疗策略是通过 非特异性机制，无法实现和维持缓解的近1/4 患有难治性疾病的儿科患者。虽然目前还没有针对ALL的靶向治疗 患者，他们可以通过干扰病理细胞和分子， 促进对多药化疗耐药的活性。蛋白激酶MEK 7表达增加 下游MAP激酶信号传导的随后放大已被确定为两个这样的过程 促进T细胞ALL（T-ALL）的化学抗性，使MEK 7成为T-ALL定向治疗的有吸引力的靶点， 治疗不幸的是，没有已知的小分子有效地和选择性地抑制这种MEK 同种型利用我们已发表的平台来询问MEK激酶家族中的抑制剂选择性， 我们设计并合成了一种显示出有效的MEK 7抑制作用的先导化合物。我的目标是 目前的建议是进一步开发和优化一种有效的和选择性的小分子MEK 7 在T-ALL模型中，用化学方法探测MAPK通路这一分支中的异常信号传导。我们 方法需要多方面的方法，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 模式，我们寻求获得新的洞察力的作用，最不了解MEK亚型的分子 T-ALL潜在的病理生理学。具有最大临床意义的是，本提案中的研究将调查 直接MEK 7抑制剂作为T-ALL靶向疗法的功效。