Targeting the menin-MLL1 complex for new therapeutics

靶向 menin-MLL1 复合物的新疗法

基本信息

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
项目类别：
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

项目摘要

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％的成年人类急性髓样白血病（AML）中，染色体重排混合谱系白血病基因（MLL，也称为MLL1，以将其与MLL2-4区分开）发生，这导致MLL融合蛋白的表达。携带MLL的白血病患者易位（以下称为MLL白血病）的预后很差，只有35％拥有5年的生存期和当前治疗方法，强调了迫切需要开发新的和 MLL白血病的更有效的治疗方法。最常见的MLL重排是平衡的MLL易位，其中仅一个MLL等位基因被截断并与70多个融合伙伴之一融合在一起。大约1400 来自MLL N末端的氨基酸都保留在所有MLL融合蛋白中，并相互作用直接与致癌辅助因子梅宁。 menin-mll蛋白 - 蛋白质相互作用是表达HOX和MEIS1基因在MLL白血病中驱动白血病的必不可少的必不可少的。因此，使用小分子靶向Menin-Mll蛋白 - 蛋白质相互作用抑制剂被认为是一个有望的，分子靶向的治疗策略治疗MLL白血病。尽管针对Menin-Mll蛋白的非肽小分子抑制剂的设计设计近年来，蛋白质相互作用已被积极追求，最好的小分子抑制剂当前可用的仅是临床前的优秀实验室研究“工具”化合物研究。开发用于治疗MLL白血病的小分子梅宁抑制剂是仍处于研究的早期阶段，没有任何化合物进展到人类的临床试验。在这是R01奖，我们建议设计和开发高潜力，具体，口服的生物利用， Menin-MLL蛋白 - 蛋白质蛋白相互作用的非肽小分子抑制剂携带MLL融合的AML处理。