Targeting the MLL-WDR5 protein-protein interaction

描述(申请人提供)：急性髓系白血病(AML)是一种血细胞正常发育受阻、细胞异常增殖的癌症。AML对儿童和成人都有影响，在美国每年大约有7000名新患者。很大一部分急性髓细胞白血病患者的预后极其糟糕。尽管在了解AML的病因方面取得了相当大的进展，但目前用于治疗这些疾病的药物在过去40年里变化不大，结果令人失望，AML患者的整体五年存活率不到20%。该项目工作的最终目标是确定治疗AML的新型药物，这些药物专门针对肿瘤细胞用来促进其生长优势的机制。具体地说，最近的研究表明，组蛋白H3K4甲基转移酶MLL及其酶活性对于白血病转化和白血病干细胞的生存都是必不可少的。此外，MLL的H3K4酶活性受到WDR5-MLL蛋白-蛋白质相互作用的严格调控。我们推测，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 H3K4甲基转移酶的活性，并有可能被开发为治疗急性白血病的一种全新的治疗方法。为了实现这一目标，我们与一群具有互补专业知识和经过验证的记录的研究人员合作，利用强大的基于结构的设计策略设计和开发高度有效和特定的WDR5-MLL相互作用小分子抑制剂。我们的初步数据为这一方法提供了关键的概念验证，并为该项目的成功奠定了基础。

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.