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Development of novel anti-leukemia agents targeting the menin-MLL interaction

开发针对 menin-MLL 相互作用的新型抗白血病药物

基本信息

批准号：
9899939
负责人：
Jolanta Grembecka
金额：
$ 37.28万
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：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899939
关键词：
Acute Acute Myelocytic Leukemia Acute leukemia Adult Affect Animals Binding Binding Sites C-terminal Cell Proliferation Cells Child Chimeric Proteins Chromosomal translocation Clinical Research Complex Crystallography Data Development Drug Kinetics Effectiveness Fusion Oncogene Proteins Future Genes Goals Grant Hematopoietic Human In Vitro Lead Leukemic Cell Lymphoblastic Leukemia MEN1 gene MLL gene Mediating Menin Metabolic Mixed-Lineage Leukemia Modeling Molecular Target N-terminal Oncogenic Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Pre-Clinical Model Property Proteins Publishing Reporting Research Resistance development Sampling Solubility Structure Survival Rate Testing Therapeutic Intervention Toxic effect Work Xenograft procedure analog base chemotherapy clinical application clinical candidate design experience hematopoietic differentiation improved in vivo in vivo Model inhibitor/antagonist innovation leukemia molecular targeted therapies mouse model nanomolar new therapeutic target novel novel therapeutic intervention novel therapeutics outcome forecast pre-clinical preclinical study preservation protein protein interaction small molecule small molecule inhibitor targeted agent

项目摘要

Chromosomal translocations of the Mixed Lineage Leukemia 1 (MLL1) gene that result in expression of MLL fusion proteins are found in about 10% of acute leukemias affecting both children and adults. Patients harboring MLL fusions have very poor prognosis, with only ~35% five-year survival rate, implying the need for development of new therapies. The MLL fusion proteins retain the N-terminal fragment of MLL, while the C- terminal portion is replaced by one out of 60 fusion partners leading to a variety of MLL fusions. Importantly, all MLL fusion proteins interact with menin, a protein encoded by the Multiple Endocrine Neoplasia 1 (MEN1) gene, and the menin-MLL fusion protein interaction is critical to the oncogenic activity of MLL fusions in leukemia. Indeed, the menin-MLL interaction has been validated in the pre-clinical models as a valuable molecular target for development of new therapies for MLL leukemia. We hypothesize that inhibition of the menin-MLL fusion protein interaction by small molecules should reverse oncogenic activity of MLL fusion proteins and inhibit progression of MLL leukemia in vivo, resulting in a new targeted therapy for MLL leukemia patients. To this end we developed small molecule inhibitors of the menin-MLL inhibitors, which represent the first small molecules reported to block this protein-protein interaction. These compounds directly binding to menin at the MLL binding site and strongly inhibit the menin-MLL interaction. We substantially optimized both potency and drug-like properties of these compounds, resulting in very potent menin-MLL inhibitors (IC50 < 15 nM, Kd < 10 nM). In MLL leukemia cells, these compounds selectively inhibit proliferation, induce differentiation and downregulate expression of MLL fusion target genes at nanomolar concentrations. Importantly, the menin- MLL inhibitors we developed (e.g. MI-503, MI-463) markedly block progression of leukemia in vivo in mice models of MLL leukemia. In this project we will continue optimization of menin-MLL inhibitors to further improve their potency and drug-like properties with the goal to develop compounds with very strong in vivo efficacy in aggressive models of MLL leukemia, including patient derived xenografts (PDX). We will also study optimal combinations of menin-MLL inhibitors with selected chemotherapy and targeted agents to identify the best combinations for future clinical studies. Furthermore, we will investigate whether resistance develops to the treatment with menin-MLL inhibitors. This work should result in very potent and selective menin-MLL inhibitors that may provide a novel therapeutic approach for the treatment of MLL leukemia patients.

混合谱系白血病1 （MLL1）基因的染色体易位导致MLL的表达