Novel lysine deacetylase 6 Hsp domain inhibitors against AML

描述（由申请人提供）：急性骨髓性白血病（AML）是最常见和最具侵袭性的急性白血病之一，每年影响30，000人。超过5年的存活率仍然保持在10- 30%左右，这在很大程度上取决于患者耐受细胞毒性化疗组合的能力，这抑制了急需的造血。目前治疗方式的局限性表明需要针对AML中相关生物靶点的创新疗法以改善临床结果。AML是一种异质性疾病;最近的研究已经确定了FLT-3、c-Kit和Ras中的一组活化激酶突变以及与疾病结局相关的组成型活性转录因子，如STAT 5和嵌合体MLL。治疗AML的主要挑战之一是开发能够影响促进AML增殖和存活的多种生物学途径的疗法。组蛋白去乙酰化酶同工酶6（HDAC 6）在AML患者中过度表达，并被假设通过调节对AML发病机制和生存至关重要的热休克蛋白功能在维持致癌信号传导中发挥关键作用。HDAC 6也是转化细胞和体内恶性细胞转化所必需的。此外，HDAC 6敲除小鼠已显示出抵抗诱变剂诱导的肿瘤并正常发育，这进一步强调了HDAC 6作为AML的耐受性更好且毒性更低的治疗靶点的潜力。我们已经确定了新的HDAC 6-热休克蛋白结构域抑制剂，优先抑制HDAC 6-热休克蛋白脱乙酰化结构域在低？M浓度和诱导Hsp 90乙酰化，不像典型的异羟肟酸HDAC 6抑制剂，tubastatin A和Tubacin。我们的总体假设是HDAC 6-Hsp结构域活性通过维持多种热休克蛋白的适当功能来促进AML增殖和存活。选择性HDAC 6-Hsp结构域抑制使多种Hsp活性失活，减弱异常AML致癌信号传导，并促进AML凋亡。该提案旨在使用多方面和创新的方法来开发新的HDAC 6-Hsp结构域抑制剂，并研究HDAC 6在AML中Hsp活性和凋亡启动的调节中所起的作用。在目标1中，我们将通过系统发育文库合成来改进我们的HDAC 6-Hsp抑制剂，以表征HDAC 6-Hsp结构域的结构活性关系。目的二是研究HDAC 6-Hsp通路轴，探讨HDAC 6依赖的Hsp 70的调控，以及Hsp 70乙酰化在溶酶体形成中的作用。最后，我们将使用生理学相关的播散性AML异种移植模型在体内检查我们的HDAC 6-Hsp脱乙酰化结构域抑制剂。我们将确定我们的主要HDAC 6抑制剂候选物对AML的疗效，对主要抑制剂候选物进行药代动力学和动态研究，并验证抑制剂影响体内生物标志物的能力。

DESCRIPTION (provided by applicant): Acute myelogenous leukemia (AML) is one of the most common and aggressive forms of acute leukemia affecting 30,000 people per year. Greater than 5 year survival rate still remains around 10-30%, and this depends greatly on the patient's ability to tolerate the combination of cytotoxic chemotherapies, which suppresses much needed haemopoiesis. The limits of current treatment modalities indicate a need for innovative therapies directed against relevant biological targets in AML to improve the clinical outcome. AML is a heterogeneous disease; recent studies have identified a set of activating kinase mutations in FLT-3, c-Kit, and Ras and constitutively active transcription factors such as STAT5 and chimera MLL relevant to disease outcome. One of the major challenges in treating AML is developing therapies that are capable of affecting multiple biological pathways promoting AML proliferation and survival. Histone deacetylase isozyme 6 (HDAC6) is over-expressed in AML patients and is hypothesized to play a key role in maintaining oncogenic signaling through the regulation of heat-shock protein functions that are critical for AML pathogenesis and survival. HDAC6 is also required for malignant cell transformation both in transformed cells and in vivo. Moreover, HDAC6 knock-out mice have been shown to resist mutagen induced tumors and develop normally, which further underscore the potential of HDAC6 as a better tolerated and less toxic therapeutic target for AML. We have identified novel HDAC6-Hsp domain inhibitors, which preferentially inhibit the HDAC6-Hsp deacetylation domain at low ?M concentration and induce Hsp90 acetylation, unlike the canonical hydroxamate HDAC6 inhibitors, tubastatin A and Tubacin. Our overarching hypothesis is that HDAC6-Hsp domain activity promotes AML proliferation and survival by maintaining proper function of multiple heat-shock proteins. Selective HDAC6-Hsp domain inhibition deactivates multiple Hsp activities, attenuates aberrant AML oncogenic signaling, and promotes AML apoptosis. This proposal intends to use multifaceted and innovative approaches to develop novel HDAC6-Hsp domain inhibitors and to investigate the role that HDAC6 plays in the regulation of Hsp activities and apoptosis initiation in AML. In Aim 1, we will refine our HDAC6-Hsp inhibitors through a phylogenetic library synthesis in order to characterize the structure activity relationship of the HDAC6-Hsp domain. In Aim 2, we will investigate the HDAC6-Hsp pathway axis, study HDAC6 dependent Hsp70 regulation, and the roles of Hsp70 acetylation play in apoptosome formation. Finally, we will examine our HDAC6-Hsp deacetylation domain inhibitors in vivo using a physiologically relevant disseminated AML xenograft model. We will determine the efficacy of our lead HDAC6 inhibitor candidates against AML, performing pharmacokinetic and dynamic studies on lead inhibitor candidates, and validate the inhibitor's ability to influence biomarkers in vivo.