Targeting IRAK1/4 in Myelodysplastic Syndromes

我实验室的研究取得了与分子、细胞、 骨髓增生异常综合征(MDS)的遗传基础是一种复杂而鲜为人知的疾病 造血干细胞衰竭综合征。MDS的复杂性和异构性，以及 缺乏小鼠模型，仍然是理解和有效治疗的主要障碍 这种病。免疫相关基因的过度表达在MDS和慢性疾病中被广泛报道 先天免疫途径的激活，主要是通过Toll样受体(TLRs)，增加了 开发MDS。多种独立的机制参与了TLR的过度激活 MDS中的信号，汇聚在涉及IRAK1、IRAK4和TRAF6的中央复合体上。 根据我们已发表的和初步的数据，IRAK1和IRAK4(IRAK1/4)是一种双激酶 复合体在MDS患者中被激活。此外，IRAK1/4-TRAF6复合体的重要性 来自我们最近的观察，描述了遗传和药理学 抑制IRAK1/4作为抑制TRAF6和MDS克隆的有效药物的途径。 总的来说，这些分子和遗传改变清楚地牵涉到IRAK1/4-TRAF6信号 作为MDS的致病驱动因素和可用药复合体。因此，我们假设 IRAK1和IRAK4的分子双重抑制剂将抑制MDS细胞的增殖。我们推导出 一种新的化学系列有效的双重IRAK1/4抑制剂。先导化合物显示出很强的药效 抑制MDS中IRAK1和IRAK4的表达及其对MDS细胞活性和功能的抑制作用 体外，在体内具有良好的药代动力学和药效学特性。因此， 这项建议的目标是优化和评估我们的候选双IRAK1/4抑制剂 体外培养的人MDS细胞(AIM 1)，以及体内的小鼠和人MDS模型(AIM 2)。这个 具体的目标将提供必要的临床前信息，关于治疗的潜力 合理设计双IRAK1/4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.