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: 10061570
• 负责人: Dalton Robert Kim
• 金额: $ 4.94万
• 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/10061570
• 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; Structure; 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/antagonist; insight; leukemia; mortality; mouse model; mutant; novel; patient derived xenograft model; pediatric patients; protein expression; 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）是儿科患者中最常见的血液性恶性肿瘤 20岁以前与癌症相关死亡率的最常见原因。当前的治疗策略由 非特异性机制在4分中近1个无法实现和维持缓解的机制 儿科患者患有耐药性疾病。虽然目前尚不适合所有目标疗法 患者，他们可以通过干扰病理细胞和分子来改善患者的预后 促进耐药性化学疗法的活动。蛋白激酶MEK7的表达增加 随之而来的下游MAP激酶信号的扩增已被确定为两个这样的过程 促进T-cell All（T-All）的化学稳定，使MEK7成为T-ALL指向的有吸引力的目标 疗法。不幸的是，没有人知道有效，有选择地抑制这种MEK的小分子 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表现出强大的MEK7抑制的铅化合物。我的目标 目前的建议是有效和选择性小分子MEK7的进一步发展和优化 在T-ALL模型中，在MAPK途径的此手臂的化学探测器异常信号传导中抑制剂。我们的 方法论需要采用多方面的方法，该方法采用跨越计算学科的策略 化学，有机合成，蛋白质生物化学和分子生物学。通过这些补充 方式，我们试图获得对分子中最低了解的MEK同工型的作用的新见解 T-ALL的病理生理学。具有最大的临床意义，该提案中的研究将调查 直接MEK7抑制剂作为T-ALL的靶向疗法的功效。