Targeting the menin-MLL1 complex for new therapeutics

靶向 menin-MLL1 复合物的新疗法

• 批准号: 9889047
• 负责人: SHAOMENG WANG
• 金额: $ 64.77万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-04 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889047
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Address; Adult; Advanced Development; Affinity; Alleles; Amino Acids; Animals; Award; Binding; Bioavailable; Biological Assay; Biological Availability; Bone Marrow Cells; Bone Marrow Stem Cell; Cell Line; Cell model; Chimeric Proteins; Chromosomal Rearrangement; Clinical Trials; Complex; Crystallization; Development; Disadvantaged; Dose; Drug Kinetics; Gene Expression; Goals; HRX protein; Homeobox Genes; Human; In Vitro; Laboratory Research; Lead; Leukemic Cell; MEIS1 gene; MLL gene; MLL2 gene; Menin; Metabolic; Molecular Mechanisms of Action; Mus; Oncogenic; Oral; Patients; Pharmacodynamics; Plasma; Property; Proteins; Reporting; Research; Schedule; Series; Solid; Specificity; Structure; Survival Rate; Therapeutic; Toxic effect; Treatment Efficacy; anticancer activity; base; cell growth; cellular targeting; clinical development; cofactor; design; fusion gene; improved; in vivo; in vivo evaluation; inhibitor/antagonist; leukemia; leukemogenesis; molecular targeted therapies; nanomolar; novel; novel therapeutics; outcome forecast; preclinical development; preclinical study; protein protein interaction; small molecule; small molecule inhibitor; success; targeted treatment; therapeutic target; tool; treatment strategy

In 5% of adult human acute myeloid leukemia (AML), chromosomal rearrangements of the mixed lineage leukemia gene (MLL, also called MLL1 to distinguish it from MLL2-4) occur, which results in expression of MLL fusion proteins. Patients with leukemia carrying a MLL translocation (hereafter also called MLL leukemia) have very poor prognosis and only 35% have a 5-year survival with current treatments, highlighting the urgent need to develop new and more effective therapeutic approaches for MLL leukemia. The most common MLL rearrangements are balanced MLL translocations, in which only one MLL allele is truncated and fused with one of over 70 fusion partners. Approximately 1400 amino acids from the MLL N-terminus are retained in all the MLL fusion proteins, and interact directly with the oncogenic cofactor menin. The menin-MLL protein-protein interaction is essential for expression of HOX and MEIS1 genes to drive leukemogenesis in MLL leukemia. Consequently, targeting the menin-MLL protein-protein interaction using small-molecule inhibitors is considered to be a promising, molecularly targeted therapeutic strategy for the treatment of MLL leukemia. Although design of non-peptide small–molecule inhibitors targeting the menin-MLL protein- protein interaction has been actively pursued in recent years, the best small-molecule inhibitors currently available are only excellent laboratory research “tool” compounds for preclinical studies. Development of small-molecule menin inhibitors for the treatment of MLL leukemia is still in an early stage of research and no compound has progressed into human clinical trials. In this R01 award, we propose to design and develop highly potent, specific, orally bioavailable, non-peptide small-molecule inhibitors of the menin-MLL protein-protein interaction for the treatment of AML carrying MLL fusion.

在5%的成人急性髓细胞白血病（AML）中， 混合谱系白血病基因（MLL，也称为MLL 1以区别于MLL 2 -4）发生， 其导致MLL融合蛋白的表达。携带MLL的白血病患者 易位型白血病（以下也称为MLL白血病）的预后非常差，仅35% 目前的治疗方法有5年的生存期，这突出了开发新的， MLL白血病的更有效的治疗方法。 最常见的MLL重排是平衡MLL易位，其中仅 一个MLL等位基因被截短并与超过70个融合配偶体之一融合。大约1400 来自MLL N-末端的氨基酸保留在所有MLL融合蛋白中，并相互作用 直接与致癌辅因子menin结合。menin-MLL蛋白-蛋白相互作用是 在MLL白血病中，HOX和MEIS 1基因的表达对驱动白血病发生至关重要。 因此，使用小分子靶向脑膜蛋白-MLL蛋白-蛋白相互作用， 抑制剂被认为是一种有前途的，分子靶向治疗策略， MLL白血病的治疗 尽管靶向menin-MLL蛋白的非肽小分子抑制剂的设计- 近年来，蛋白质相互作用一直是人们积极追求的，最好的小分子抑制剂 目前可获得的仅是用于临床前研究的优秀实验室研究“工具”化合物， 问题研究用于治疗MLL白血病的小分子menin抑制剂的开发是 仍处于研究的早期阶段，没有化合物进入人体临床试验。在 这个R 01奖，我们建议设计和开发高效，特异性，口服生物利用度， MLL蛋白-蛋白相互作用的非肽小分子抑制剂， 治疗携带MLL融合的AML。