Targeting IRAK1/4 in Myelodysplastic Syndromes

我实验室的研究已经取得了与分子，细胞， 骨髓增生异常综合征（MDS）是一种复杂且知之甚少的疾病， 造血干细胞（HSC）衰竭综合征。MDS的复杂性和异质性，以及 缺乏小鼠模型仍然是理解和有效治疗的主要障碍 这种疾病。免疫相关基因的过度表达在MDS中被广泛报道，并且慢性骨髓增生异常综合征（MDS）患者的免疫相关基因的过度表达在MDS中被广泛报道。 先天免疫途径的激活，主要是通过Toll样受体（TLR），增加了 发展MDS。多种独立机制导致TLR过度激活 MDS中的信号传导，其汇聚在涉及IRAK 1、IRAK 4和TRAF 6的中心复合物上。 根据我们发表的和初步的数据，IRAK 1和IRAK 4（IRAK 1/4），一种双重激酶， 在MDS患者中，复合物被激活。此外，IRAK 1/4-TRAF 6复合物的重要性 来自我们最近的观察，描述了遗传和药理学 抑制IRAK 1/4的方法作为抑制TRAF 6和MDS克隆的有效药剂。 总的来说，这些分子和遗传改变清楚地暗示了IRAK 1/4-TRAF 6信号转导 作为MDS的致病驱动因素和药物复合物。因此，我们假设， IRAK 1和IRAK 4的分子双重抑制剂将抑制MDS增殖细胞。推导出 一种新的化学系列的有效双重IRAK 1/4抑制剂。先导化合物显示出 MDS中IRAK 1和IRAK 4的抑制，在MDS中抑制MDS细胞活力和功能的功效， 体外，和有前途的药代动力学和药效学特性在体内。因此， 本提案的目的是优化和评估我们的候选双重IRAK 1/4抑制剂， 体外人MDS细胞（Aim 1）和体内小鼠和人MDS模型（Aim 2）。的 具体的目的将提供必要的临床前信息的治疗潜力， 合理设计的双重IRAK 1/4抑制剂用于未来的人类MDS试验。

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.