Anti-ALL Small Molecular Discovery via Chemical Genomics

通过化学基因组学发现抗 ALL 小分子

• 批准号: 7478491
• 负责人: TODD R. GOLUB
• 金额: $ 23.28万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7478491
• 关键词: Academia; Acute; Acute Lymphocytic Leukemia; Area; Biological; Biology; Cells; Chemicals; Child; Clinical; Clinical Trials; Collection; Cytotoxic agent; Databases; Development; Development, Other; Disease; Drug Compounding; Event; Gene Expression; Gene Expression Profile; Generic Drugs; Genetic; Genomics; Glucocorticoids; Industry; Laboratories; Lymphoblastic Leukemia; Maps; Marketing; Measures; Methods; Molecular; Molecular Genetics; Molecular Profiling; Mutation; Myelogenous; Output; Patients; Pharmacologic Substance; Population; Process; Reporting; Research Personnel; Resistance; Screening procedure; Solutions; Standards of Weights and Measures; TEL-AML1 Fusion Protein; Therapeutic; Toxic effect; Translations; Ursidae Family; Validation; Work; base; chemical genetics; chemotherapy; cost; drug discovery; high throughput screening; inhibitor/antagonist; insight; interest; leukemia; novel strategies; novel therapeutics; preclinical study; programs; small molecule; tool; transcription factor

A key challenge in moving from a genetic understanding of disease to effective therapeutics is the identification of functionally validated effectors of the process, against which small molecule inhibitors can be developed. The challenge in the case of acute lymphoblastic leukemia (ALL) is that such effectors are not known. The drug discovery challenge in ALL is compounded by the fact that ALL does not represent an attractive market for industry, thus shifting the burden of early chemical discovery to academia. We propose here a chemical genomic solution whereby a small molecule screen is performed based on the ability of compounds to modulate a gene expression program of interest. This is based on our recently reported Gene Expression-Based High Throughput Screening (GE-HTS) method wherein we demonstrated that we could identify small molecules capable of inducing myeloid differentiation of AML cells based on their ability to trigger a gene expression signature of interest. We now propose to extend this approach to three important areas of ALL biology. In Aim 1, we will define a gene expression signature of TEL/AML1 activity, and we will attempt to identify compounds capable of reversing the TEL/AML1 gene expression program. Such compounds would be a starting point for molecularly targeted therapy for TEL/AML1 positive patients. In Aim 2, we will similarly attempt to identify compounds capable of reversing the molecular program of MLL mutation as a means of exploring therapeutic approaches for MLL-rearranged leukemias. Lastly, in Aim 3 we will screen for chemicals capable of modulating glucocorticoid sensitivity in ALL cells. Such molecules would have great utility both as biological tool compounds with which to better understand the biology of glucocorticoid sensitivity, and may also suggest therapeutic strategies for ALL patients unlikely to respond to standard therapy.

从对疾病的遗传理解转变为有效疗法的关键挑战是 鉴定该过程的功能验证效应子，小分子抑制剂可以是 发达。在急性淋巴细胞白血病的情况下（全部）挑战是，这种效应者不是 已知。所有人都不代表一个事实，总体而言，毒品发现挑战的加剧了 有吸引力的工业市场，从而将早期化学发现的负担转移到了学术界。我们建议 在这里，一种化学基因组溶液，从而根据该溶液进行小分子筛选的能力 化合物调节感兴趣的基因表达程序。这是基于我们最近报道的基因 基于表达的高吞吐量筛选（GE-HTS）方法，其中我们证明我们可以识别能够诱导髓样分化的小分子 AML细胞基于它们触发感兴趣的基因表达特征的能力。我们现在建议 将此方法扩展到所有生物学的三个重要领域。在AIM 1中，我们将定义一个基因表达 TEL/AML1活动的签名，我们将尝试识别能够逆转的化合物 Tel/AML1基因表达程序。这样的化合物将是分子靶向的起点 TEL/AML1阳性患者的治疗。在AIM 2中，我们将类似地尝试识别能够的化合物 逆转MLL突变的分子程序，作为探索MLL重新培训的治疗方法的一种手段 白血病。最后，在AIM 3中，我们将筛选能够调节糖皮质激素的化学物质 所有细胞的敏感性。这样的分子将具有很大的实用性，因为 这可以更好地理解糖皮质激素敏感性的生物学，也可能提出治疗性 所有患者的策略不太可能对标准疗法做出反应。