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: 7893021
• 负责人: TODD R. GOLUB
• 金额: $ 24.21万
• 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/7893021
• 关键词: Academia; Acute Lymphocytic Leukemia; Area; Biological; Biology; Cells; Chemicals; Child; Clinical; Clinical Trials; Collection; Cytotoxic agent; Databases; Development; Disease; Drug Compounding; Event; FDA approved; Gene Expression; Gene Expression Profile; Generic Drugs; Genetic; Genomics; Glucocorticoids; Industry; Laboratories; Maps; Marketing; Measures; Methods; Molecular; Molecular Genetics; Molecular Profiling; Mutation; Myelogenous; Output; Patients; Pharmacologic Substance; Process; Reporting; Research Personnel; Resistance; Screening procedure; Solutions; TEL-AML1 Fusion Protein; Therapeutic; Therapeutic Index; 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; patient population; 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向有效治疗的一个关键挑战是 鉴定该过程中经过功能验证的效应器，可以针对该效应器进行小分子抑制剂 发达。急性淋巴细胞白血病 (ALL) 的挑战在于，此类效应器不能发挥作用。 已知。 ALL 并不代表一种疾病，这一事实使 ALL 的药物发现挑战变得更加复杂。 对工业界有吸引力的市场，从而将早期化学发现的负担转移给学术界。我们建议 这是一种化学基因组解决方案，根据以下能力进行小分子筛选： 调节感兴趣的基因表达程序的化合物。这是基于我们最近报道的基因 基于表达的高通量筛选（GE-HTS）方法，我们证明我们可以鉴定能够诱导骨髓分化的小分子 基于 AML 细胞触发感兴趣的基因表达特征的能力。我们现在建议 将这种方法扩展到所有生物学的三个重要领域。在目标 1 中，我们将定义一个基因表达 TEL/AML1 活性的特征，我们将尝试识别能够逆转 TEL/AML1 活性的化合物 TEL/AML1 基因表达程序。此类化合物将成为分子靶向的起点 TEL/AML1 阳性患者的治疗。在目标 2 中，我们将同样尝试识别能够 逆转 MLL 突变的分子程序作为探索 MLL 重排治疗方法的一种手段 白血病。最后，在目标 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。这些分子作为生物工具化合物具有很大的用途 这可以更好地了解糖皮质激素敏感性的生物学，并且还可以建议治疗 针对不太可能对标准治疗产生反应的所有患者的策略。