Targeting the ENL YEATS domain for the development of anti-leukemia agents

项目摘要/摘要 急性髓系白血病(AML)是一种以快速增殖和 未成熟的髓样细胞积聚，不能分化成正常的血细胞。作为世界上 AML是白血病中最致命的亚型，通常由融合多个谱系的染色体易位驱动 白血病基因MLL1与含有叶芝结构域的蛋白EN1或AF9的任一结合。最近的研究表明 提示ENL而不是AF9对MLL重排白血病细胞的维持是必需的，使ENL 作为急性髓系白血病治疗学发展的有价值的靶点。恩尔·叶芝的领域起着至关重要的作用 染色质中组蛋白赖氨酸乙酰化的识别。通过开发选择性靶向的小分子 Enl Yeats结构域抑制其对染色质中组蛋白乙酰化的识别，多种化合物 已发现可抑制MLL重排白血病细胞的生长。受到这一强劲的初步调查的鼓舞 研究，目前的应用集中在扩大药物发现的努力，靶向ENL为 追求三个短期特定目标的MLL重排白血病治疗药物的发展。在第一个 目的，将开发用于ENL及其近亲AF9的NanoBRET系统，用于ENL抑制剂的分析 它们的细胞渗透性、稳定性、选择性和药物在细胞内的滞留时间。在第二个目标中，彻底 将对开发的小分子ENL抑制剂进行表征，并将获得知识 用于开发具有更高效力和选择性的新型缓蚀剂。在第三个目标中，目前 蛋白质水解靶向嵌合体(Protac)这一蓬勃发展的药物发现概念将被应用于enl药物。 为开发ENL靶向PROTAC分子所做的发现工作。这个项目的成功将使 一些潜在的MLL重排白血病治疗药物可用于进一步的临床前和临床 评估。

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a hematological cancer characterized by the quick proliferation and accumulation of immature myeloid cells that are impaired to differentiate into normal blood cells. As one of the deadliest subtypes of leukemia, AML is often driven by chromosomal translocations that fuse the multiple lineage leukemia gene MLL1 to either of the YEATS domain-containing proteins, ENL or AF9. Recent studies have indicated that ENL but not AF9 is essential for the maintenance of MLL-rearranged leukemia cells, making ENL as a valuable target for the development of therapeutics for AML. The ENL YEATS domain serves a critical role in the recognition of histone lysine acetylation in chromatin. By developing small molecules that selectively target the ENL YEATS domain to inhibit its recognition of histone acetylation in chromatin, multiple compounds have been identified that inhibit the growth of MLL-rearranged leukemia cells. Encouraged by this strong preliminary study, the current application is focused on expanding the drug discovery endeavor in targeting ENL for the development of MLL-rearranged leukemia therapeutics by pursuing three short-term specific aims. In the first aim, NanoBRET systems will be developed for ENL and its close paralogue AF9 for the analysis of ENL inhibitors in their cellular permeability, stability, selectivity, and drug residence time in cells. In the second aim, thorough characterization of developed small molecule ENL inhibitors will be conducted and obtained knowledge will be used for the development of novel inhibitors with improved potency and selectivity. In the third aim, a currently booming drug discovery concept, proteolysis targeting chimera (PROTAC), will be applied to the ENL drug discovery effort for the development of ENL-targeting PROTAC molecules. The success of the project will make a number of potential MLL-rearranged leukemia therapeutics available for further preclinical and clinical evaluations.