Targeting IRAK1/4 in Myelodysplastic Syndromes

靶向治疗骨髓增生异常综合征中的 IRAK1/4

基本信息

批准号：
9301788
负责人：
Daniel Starczynowski
金额：
$ 49.12万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-07 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9301788
关键词：
Acute Myelocytic Leukemia Acute leukemia Allogenic Applications Grants Automobile Driving Binding Sites Biological Assay Blood Blood Cells Bone Marrow Cell Line Cell Survival Cell physiology Cells Chemicals Chronic Clinical Clonal Hematopoietic Stem Cell Collection Complex Congenital Disorders Data Development Disease Disease regression Drug Kinetics Dysmyelopoietic Syndromes Dysplasia Evolution Exhibits Failure Future Genes Genetic Goals Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Heterogeneity Human IRAK1 gene IRAK4 gene Immune In Vitro Inherited Laboratories Lead Life Expectancy Malignant Neoplasms Mediator of activation protein Modality Modeling Molecular Molecular Genetics Monitor Mus Mutation Myelogenous Myeloid Cells Pathogenesis Pathogenicity Pathology Pathway interactions Patients Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacology Phosphorylation Phosphotransferases Property Publications Publishing Receptor Signaling Reporting Research Risk Sampling Series Signal Transduction Syndrome TRAF6 gene Therapeutic Toll-Like Receptor Pathway Toll-like receptors Toxic effect Treatment Efficacy Xenograft Model Xenograft procedure base chemotherapy cytopenia design effective therapy immunoregulation improved in vivo in vivo Model inhibitor/antagonist mouse model novel novel therapeutics overexpression pre-clinical progenitor pyridine scaffold small molecule

项目摘要

Research in my laboratory has made critical findings related to the molecular, cellular, and genetic basis of Myelodysplastic Syndromes (MDS), a complex and poorly understood hematopoietic stem cell (HSC) failure syndrome. The complexity and heterogeneity of MDS, and the lack of mouse models, remain as major obstacles to understanding and effectively treating this disease. Overexpression of immune-related genes is widely reported in MDS, and chronic innate immune pathway activation, primarily via Toll-like receptors (TLRs), increases the risk of developing MDS. Multiple independent mechanisms contribute to hyperactivation of TLR signaling in MDS, which converge on the central complex involving IRAK1, IRAK4, and TRAF6. Based on our published and preliminary data, IRAK1 and IRAK4 (IRAK1/4), a dual kinase complex is activated in MDS patients. Moreover, the importance of the IRAK1/4-TRAF6 complex in primary MDS comes from our recent observation that describes genetic and pharmacologic approaches to inhibit IRAK1/4 as effective agents to suppress TRAF6 and the MDS clone. Collectively, these molecular and genetic alterations clearly implicate IRAK1/4-TRAF6 signaling as a pathogenic driver and druggable complex in MDS. Therefore, we hypothesize that small molecule dual inhibitors of IRAK1 and IRAK4 will suppress MDS-propagating cells. We derived a novel chemical series of potent dual IRAK1/4 inhibitors. The lead compound shows potent inhibition of IRAK1 and IRAK4 in MDS, efficacy at suppressing MDS cell viability and function in vitro, and promising pharmacokinetic and pharmacodynamics properties in vivo. As such, the objective of this proposal is to optimize and evaluate our candidate dual IRAK1/4 inhibitors in human MDS cells in vitro (Aim 1), and in mouse and human MDS models in vivo (Aim 2). The specific aims will provide necessary preclinical information on the therapeutic potential of rationally designed dual IRAK1/4 inhibitors for future human MDS trials.

我的实验室的研究提出了与分子，细胞相关的关键发现和骨髓增生综合征（MDS）的遗传基础，这是一种复杂而鲜为人知的造血干细胞（HSC）衰竭综合征。 MD的复杂性和异质性，以及缺乏鼠标模型，仍然是理解和有效治疗的主要障碍这种疾病。在MDS中广泛报道了与免疫相关基因的过表达，慢性先天免疫途径激活，主要是通过Toll样受体（TLR）增加开发MD。多种独立机制导致TLR过度激活 MDS中的信号传导在涉及IRAK1，IRAK4和TRAF6的中央复合体上收敛。根据我们已发布和初步数据，IRAK1和IRAK4（IRAK1/4），双激酶 MDS患者激活复合物。此外，IRAK1/4-TRAF6综合体的重要性在初级MD中，我们最近的观察结果描述了遗传学和药物。抑制IRAK1/4作为抑制TRAF6和MDS克隆的有效药物的方法。总的来说，这些分子和遗传改变明显暗示了IRAK1/4-TRAF6信号传导作为MDS中的病原驱动器和可药物复合物。因此，我们假设这很小 IRAK1和IRAK4的分子双抑制剂将抑制MDS传播细胞。我们得出一系列有效的双IRAK1/4抑制剂的新型化学化学系列。铅化合物显示有效抑制irak1和irak4在MDS中，抑制MDS细胞活力和功能的功效体内的体外药代动力学和药效学特性。因此，该建议的目的是优化和评估我们的候选双IRAK1/4抑制剂人体MDS细胞体外（AIM 1）以及在体内的小鼠和人类MDS模型中（AIM 2）。这具体目的将提供有关治疗潜力的必要临床前信息为未来的人类MDS试验进行合理设计的双IRAK1/4抑制剂。