Targeting Menin in Acute Leukemia with Upregulated HOX Genes

通过上调 HOX 基因靶向急性白血病中的 Menin

基本信息

批准号：
10655162
负责人：
Jolanta Grembecka
金额：
$ 63.35万
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：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655162
关键词：
3-Dimensional Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute leukemia Adult Affect Animals Binding Binding Sites Biological Child Chimeric Proteins Chromosomal translocation Clinical Clinical Data Clinical Research Clinical Trials Collaborations Complex Crystallography Data Development Disease remission Down-Regulation Drug Kinetics Drug Targeting FDA approved Foundations Future Genes Goals Growth HOXA9 gene Homeobox Genes Lead Leukemic Cell MEIS1 gene Menin Metabolic Mixed-Lineage Leukemia Modeling Molecular Conformation Mutate Mutation N-terminal Nuclear Pore Complex Proteins Oncogenic Oncology Outcome Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phase Play Prognosis Proliferating Property Proteins Remission Induction Reporting Resistance development Role Sampling Solubility Structure Survival Rate Toxic effect Up-Regulation Work Xenograft procedure analog clinical candidate clinical translation clinically relevant design effectiveness evaluation improved in vivo inhibitor interdisciplinary approach leukemia leukemia treatment leukemogenesis mouse model nanomolar new therapeutic target next generation novel novel therapeutics nucleophosmin patient derived xenograft model protein protein interaction recruit scaffold side effect small molecule small molecule inhibitor therapeutic target

项目摘要

Abstract The protein-protein interaction between menin and Mixed Lineage Leukemia 1 (MLL1) protein plays a critical role in acute leukemia with chromosomal translocations of the MLL1 gene, affecting both children and adults. Leukemia patients with MLL1 translocations have very poor prognosis, with only ~35% five-year survival rate, implying an urgent need for new therapies. The menin-MLL1 interaction also plays an important role in acute myeloid leukemia (AML) with mutations in the nucleophosmin 1 (NPM1) gene and with chromosomal translocations of the Nucleoporin 98 (NUP98) gene, both are associated with very poor prognosis in patients. The interaction of menin with MLL1 is required for the recruitment of MLL1 and MLL fusion proteins to the target genes (e.g. HOXA and MEIS1 genes), which are critical to leukemogenesis in the MLL1-rearranged, NPM1- mutated and NUP98-rearranged leukemias. Thus, the menin-MLL1 interaction plays a critical role in acute leukemia with upregulated HOX genes, constituting ~50% of all acute leukemia cases, supporting that small molecule inhibition of this interaction might provide new targeted therapy for leukemia patients. We pioneered development of small molecule inhibitors of the menin-MLL1 interaction, which directly bind to menin at the MLL1 binding site and strongly inhibit this protein-protein interaction. Subsequent medicinal chemistry optimization resulted in advanced menin-MLL1 inhibitors, such as MI-3454, with sub-nanomolar activity and high selectivity. MI-3454 demonstrates very pronounced activity in the MLL1-rearranged and NPM1-mutated leukemia models, blocking proliferation and inducing differentiation of leukemic cells through downregulation of HOX and MEIS1 genes, and strongly blocks leukemia progression in vivo in AML models, including complete remission. We have also developed and substantially optimized a new class of menin-MLL1 inhibitors that belong to a novel scaffold that fits very well to the MLL1 binding site on menin. These compounds have very pronounced activity in blocking the menin-MLL1 interaction and demonstrate strong effect in leukemia models, representing very attractive candidates to identify clinically relevant compounds with improved drug-like properties. In this project we propose to develop the next generation of menin inhibitors with picomolar activity derived from our advanced lead compounds for their clinical translation to AML patients. We will apply highly interdisciplinary approach, involving medicinal chemistry, structure-based design, pharmacokinetic (PK) studies and biological studies to develop highly optimized compounds with very strong in vivo efficacy in aggressive models of high HOXA leukemia, such as patient derived xenograft (PDX) models of AML, and with optimized drug-like properties. We will also study optimal combinations of our next generation of menin-MLL1 inhibitors with other agents to identify the best combinations for future clinical studies. We expect this work should result in the next generation of menin-MLL1 inhibitors with superior activity and drug-like properties over existing menin inhibitors that will be very attractive for clinical translation to leukemia patients

抽象的 Menin和混合谱系白血病1（MLL1）蛋白之间的蛋白质 - 蛋白质相互作用起着关键在急性白血病中具有MLL1基因染色体易位的作用，影响儿童和成人。 MLL1易位的白血病患者的预后较差，五年生存率仅为35％，意味着迫切需要新疗法。 Menin-Mll1相互作用在急性中也起着重要作用髓样白血病（AML）具有核磷酸1（NPM1）基因中的突变和染色体核孔蛋白98（NUP98）基因的易位都与患者的预后非常差有关。 Menin与MLL1的相互作用是募集MLL1和MLL融合蛋白与靶标需要的基因（例如HOXA和MEIS1基因），对MLL1重新传播的白血病至关重要，NPM1- 突变和NUP98重新培养的白血病。因此，Menin-Mll1相互作用在急性中起着至关重要的作用白血病具有上调的HOX基因，占所有急性白血病病例的约50％，支持这一小这种相互作用的分子抑制可能为白血病患者提供新的靶向疗法。我们开创了 Menin-Mll1相互作用的小分子抑制剂的发展，该抑制剂直接与MLL1的Menin结合结合位点并强烈抑制这种蛋白质蛋白质相互作用。随后的药物化学优化产生了晚期MENIN-MLL1抑制剂，例如MI-3454，具有亚纳米摩尔活性和高选择性。 MI-3454在MLL1重建和NPM1突变的白血病模型中表现出非常明显的活性，通过下调HOX和MEIS1，阻止增殖并诱导白血病细胞的分化基因，强烈阻止AML模型中体内的白血病进展，包括完全缓解。我们有还开发并实质上优化了属于新型脚手架的新类Menin-Mll1抑制剂这非常适合Menin上的MLL1结合位点。这些化合物在阻塞时具有非常明显的活性 Menin-Mll1相互作用并在白血病模型中表现出强烈的作用，代表了非常吸引人的候选者可以鉴定具有改善类似药物的特性的临床相关化合物。在这个项目中，我们建议开发下一代的Menin抑制剂，具有从我们先进的铅中得出的皮摩尔活性其临床翻译为AML患者的化合物。我们将采用高度跨学科的方法，涉及药物化学，基于结构的设计，药代动力学（PK）研究和生物学研究高度优化的化合物在高HOXA白血病的侵略性模型中具有非常强大的体内功效，作为AML的患者衍生的异种移植（PDX）模型，并具有优化的药物样特性。我们还将学习我们下一代Menin-Mll1抑制剂与其他代理商的最佳组合，以识别最好的将来临床研究的组合。我们希望这项工作应该导致下一代Menin-Mll1 与现有的MENIN抑制剂相比，具有出色活性和类似药物的抑制剂将非常有吸引力用于白血病患者的临床翻译