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% 的成人急性髓系白血病 (AML) 中，混合谱系白血病基因（MLL，也称为 MLL1，以区别于 MLL2-4），导致携带 MLL 的白血病患者表达 MLL 融合蛋白。易位（以下也称为 MLL 白血病）预后极差，仅有 35% 目前的治疗方法可实现 5 年生存，这凸显了开发新疗法的迫切需要 MLL 白血病更有效的治疗方法。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 70 多个融合伙伴之一融合。 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助因子 menin 相互作用。对于 HOX 和 MEIS1 基因的表达驱动 MLL 白血病的白血病发生至关重要。经过测试，使用小分子靶向 menin-MLL 蛋白质-蛋白质相互作用抑制剂被认为是一种有前景的分子靶向治疗策略治疗 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目前可用的只是用于临床前的优秀实验室研究“工具”化合物研究开发了用于治疗 MLL 白血病的小分子 menin 抑制剂。仍处于研究的早期阶段，尚未有化合物进入人体临床试验。在这个 R01 奖中，我们建议设计和开发高效、特异、口服生物可利用的、 menin-MLL 蛋白-蛋白相互作用的非肽小分子抑制剂携带 MLL 融合的 AML 的治疗。