权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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%的成人急性髓性白血病（AML）中，染色体重排