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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

摘要 menin和混合谱系白血病1（MLL 1）蛋白之间的蛋白质-蛋白质相互作用在白血病的发病中起着关键作用。 MLL 1基因在急性白血病染色体易位中的作用，影响儿童和成人。 MLL 1易位的白血病患者预后非常差，5年生存率仅为~35%，这意味着迫切需要新的治疗方法。menin-MLL 1相互作用也在急性脑梗死中起重要作用。具有核磷蛋白1（NPM 1）基因突变和染色体异常的髓性白血病（AML）核孔蛋白98（NUP 98）基因的易位，两者都与患者的非常差的预后相关。 menin与MLL 1的相互作用是将MLL 1和MLL融合蛋白募集到靶点所必需的基因（例如HOXA和MEIS 1基因），它们对MLL 1重排的白血病发生至关重要，突变和NUP 98重排的白血病。因此，menin-MLL 1相互作用在急性炎症中起着关键作用。 HOX基因上调的白血病，占所有急性白血病病例的约50%，支持小分子抑制这种相互作用可能为白血病患者提供新的靶向治疗。我们开创开发menin-MLL 1相互作用的小分子抑制剂，其在MLL 1处直接结合menin 结合位点，并强烈抑制这种蛋白质-蛋白质相互作用。后续药物化学优化导致了先进的menin-MLL 1抑制剂，如MI-3454，具有亚纳摩尔活性和高选择性。 MI-3454在MLL 1重排和NPM 1突变的白血病模型中表现出非常显著的活性，通过下调HOX和MEIS 1阻断白血病细胞增殖和诱导分化基因，并在AML模型中体内强烈阻断白血病进展，包括完全缓解。我们有我还开发并实质性优化了属于新型支架的一类新的menin-MLL 1抑制剂这非常符合MLL 1在menin上的结合位点。这些化合物具有非常显著的阻断 menin-MLL 1相互作用，并在白血病模型中显示出强作用，代表非常有吸引力候选物以鉴定具有改善的药物样性质的临床相关化合物。在这个项目中，我们建议开发具有皮摩尔活性的下一代menin抑制剂，这些化合物用于其向AML患者的临床转化。我们将采用高度跨学科的方法，包括药物化学、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白血病的侵袭性模型中具有非常强的体内功效，作为AML的患者来源的异种移植物（PDX）模型，并且具有优化的药物样性质。我们还将研究我们的下一代menin-MLL 1抑制剂与其他药物的最佳组合，以确定最佳的用于未来的临床研究。我们希望这项工作能产生下一代menin-MLL 1 具有优于现有menin抑制剂的上级活性和药物样性质的抑制剂，用于白血病患者的临床转化