Targeting the MLL-WDR5 protein-protein interaction

靶向 MLL-WDR5 蛋白质-蛋白质相互作用

• 批准号: 8536046
• 负责人: Yali Dou
• 金额: $ 46.82万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-09 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536046
• 关键词: Accounting; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Adult; Affect; Affinity; Alleles; Binding; Binding Sites; Biochemical; Biological Assay; Blood Cells; Bone Marrow Cells; Cell Line; Cells; Child; Chimeric Proteins; Complex; DNA Methyltransferase; DNA Modification Methylases; DNA Sequence Rearrangement; Data; Development; Disease; Drug Kinetics; Enzymes; Epigenetic Process; Foundations; Genes; Goals; Growth; HRX protein; Hematopoietic Neoplasms; Histone H3; Histones; Homeobox Genes; Human; Incidence; Lead; Little' s Disease; Lysine; MLL-AF9; MLL2 gene; Malignant Neoplasms; Mediating; Methyltransferase; Modeling; Molecular; Molecular Mechanisms of Action; Mus; Mutation; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Plasma; Play; Proliferating; Property; Research; Research Personnel; Role; Route; Specificity; Structure; Survival Rate; Therapeutic; Transcriptional Activation; Transferase; Transplantation; Work; Xenograft Model; anticancer activity; base; cell growth; cellular transduction; clinical efficacy; design; effective therapy; fusion gene; gain of function mutation; histone methyltransferase; improved; in vivo; infancy; inhibitor/antagonist; interest; leukemia; leukemic stem cell; leukemogenesis; neoplastic cell; novel strategies; novel therapeutic intervention; outcome forecast; overexpression; protein protein interaction; public health relevance; reconstitution; small molecule; success; therapeutic development; therapeutic target

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is a form of cancer in which the normal development of blood cells is blocked and the cells abnormally proliferate. AML affects both children and adults with an incidence of approximately 7000 new patients in the U.S. each year. A substantial portion of AMLs cases has extremely dire prognosis. Although considerable progress has been made in understanding the causes of AML, the drugs currently used to treat these diseases are little changed over the past 40 years and yield disappointing results, with an overall five-year survival rate of AML patients less than 20%. The ultimate goal of this project work is to identify new class of drugs for AML that specifically target mechanisms that the tumor cells use to promote their growth advantage. Specifically, recent studies have shown that histone H3 K4 methyltransferase MLL and its enzymatic activity are essential for both leukemic transformation and for survival of leukemic stem cells. Furthermore, the H3 K4 enzymatic activity of MLL is tightly regulated by the WDR5-MLL protein-protein interaction. We hypothesize that small- molecule inhibitors designed to block the WDR5-MLL interaction may be effective in inhibition of the MLL H3 K4 methyltransferase activity and may have the therapeutic potential to be developed as a completely new class of therapy for the treatment of acute leukemia. Toward this goal we have teamed up with a group of investigators with complementary expertise and proven record to design and develop highly potent and specific small-molecule inhibitors of the WDR5-MLL interaction using a powerful structure-based design strategy. Our preliminary data have provided the critical proof-of-concept for this approach and laid the foundation for the success of this project.

描述（由申请人提供）：急性髓样白血病（AML）是一种癌症的一种形式，其中血细胞的正常发育被阻断，细胞异常增殖。 AML每年在美国大约有7000名新患者的发病率影响儿童和成人。 AMLS病例的很大一部分具有极高的预后。尽管在理解AML的原因方面取得了很大的进展，但在过去40年中，目前用来治疗这些疾病的药物几乎没有改变，结果令人失望，而AML患者的总体五年生存率少于20％。该项目工作的最终目标是确定AML的新药物，这些药物专门针对肿瘤细胞用来促进其生长优势的机制。具体而言，最近的研究表明，组蛋白H3 K4甲基转移酶MLL及其酶促活性对于白血病转化和白血病干细胞的存活至关重要。此外，MLL的H3 K4酶活性受WDR5-MLL蛋白 - 蛋白质相互作用的严格调节。我们假设旨在阻断WDR5-MLL相互作用的小分子抑制剂可能有效地抑制MLL H3 K4甲基转移酶活性，并且可能具有开发为全新的疗法治疗急性白血病的治疗疗法。为了实现这一目标，我们与一组具有互补专业知识的调查员合作，并通过使用强大的基于结构的设计策略来设计和开发WDR5-MLL相互作用的高效和特定的小分子抑制剂。我们的初步数据为这种方法提供了关键的概念概念，并为该项目的成功奠定了基础。