Nonpeptide macrocyclic histone deacetylase (HDAC) inhibitors for targeted lung ca

描述(申请人提供)：我们寻求鉴定新型非肽大环组蛋白脱乙酰酶(HDAC)抑制剂作为一类新的抗癌药物。HDAC抑制剂在癌症治疗中有很大的前景，因为它们被证明有能力阻止几乎所有转化细胞类型的增殖。然而，这些药物中的大多数都是所有HDAC亚型的非选择性抑制剂；而且大量已鉴定的HDAC抑制剂还没有超过临床前的特征。我们的假设是，用特定的非肽大环替代物取代典型的环肽HDAC抑制剂的多肽部分，将产生一类新的有效的HDAC抑制剂，其治疗指数将得到改善。由于附加的大环部分提供了选择性的组织分布，这些化合物预计也具有靶向抗癌活性。在初步结果中，已鉴定了一类大环异羟甲酸酯。本应用的目的是研究这些化合物体外抗HDAC和抗肿瘤活性的分子机制。目的1是开发新型非肽大环HDAC抑制剂。这里的第一步是扩大我们的设计方法，包括其他结构相似的大环模板，以便创建一个工具集，随后的结构活性关系(SAR)研究将基于该工具集。为了指导这项工作，我们将使用分子对接(AutoDock)来研究这些大环模板与关键的HDAC抑制剂药效团结合的SAR。目的2描述体外和全细胞HDAC抑制的结构和生化要求。为此，我们将利用体外HDAC抑制试验和人肺癌细胞株的全细胞活性，从对接实验产生的优先列表中获得化合物的抗HDAC活性。此外，我们将基于p21WAF1/CIP1和HDAC7基因的细胞内状态以及组蛋白乙酰化模式来评估我们有效的抑制剂的全细胞机制。我们的目标3是研究铅化合物在小鼠体内的器官分布和药效。我们将首先研究健康雄性Balb/c小鼠的复合器官分布行为。然后，具有良好药代动力学参数的具有肺选择性蓄积的化合物将被推进到携带特定肺癌异种移植模型的Balb/c(nu/nu)小鼠的体内疗效研究。从长远来看，我们将确定一系列新的HDAC抑制剂，这些药物将被推进到进一步的临床前/临床评估。此外，拟议的研究将对HDAC在癌症病因学中的作用产生新的见解。与公共健康相关：肺癌是美国癌症死亡的主要原因。该提案概述了一种方法，该方法将能够识别具有肺选择性抗癌活性的新型化疗药物，用于靶向肺癌治疗。我们提出的方法有望产生更好的治疗指数的化疗药物，并将显著影响患者的生存和预后，并为人类健康管理做出积极贡献。

DESCRIPTION (provided by applicant): We seek to identify novel nonpeptide macrocyclic histone deacetylase (HDAC) inhibitors as a new class of anticancer agents. HDAC inhibitors hold great promise in cancer therapy due to their demonstrated ability to arrest proliferation of nearly all transformed cell types. However, most of these agents are non-selective inhibitors of all HDAC isoforms; and a large number of the identified HDAC inhibitors have not progressed beyond preclinical characterizations. Our hypothesis in this proposal is that substitution of the peptide moiety of a prototypical cyclic- peptide HDAC inhibitor with specific non-peptidyl macrocyclic surrogates will generate a new class of potent HDAC inhibitors with improved therapeutic index. These compounds are anticipated to also possess targeted anti-cancer activity due to selective tissue distribution conferred by the appended macrocyclic moiety. In Preliminary Results a class of macrocyclic hydroxamates has been identified. The goal of this application is to study the molecular mechanisms underlying the in vitro anti-HDAC and anti-tumor activities of these compounds. Aim 1 is to develop novel nonpeptide macrocyclic HDAC inhibitors. The first step here is to broaden our design approach to include other structurally similar macrocyclic templates in order to create a tool set upon which subsequent structure activity relation (SAR) studies will be based. To guide this effort, we will use molecular docking (AutoDock) to investigate the SAR of the combination of these macrocyclic templates with key HDAC inhibitor pharmacophores. Aim 2 is to characterize the structural and biochemical requirements for in vitro and whole cell HDAC inhibition. Toward this end, we will profile the anti-HDAC activity of compounds obtained from the priority list generated by the docking experiments using both in vitro HDAC inhibition assay and whole cell activity in human lung cancer cell lines. Moreover, we will evaluate the whole cell mechanism of our potent inhibitors based on intracellular status of p21WAF1/CIP1 and HDAC7 genes, and histone protein acetylation patterns. Our Aim 3 is to investigate the organ distribution and in vivo efficacy of lead compounds in mice. We will first study compound organ distribution behavior in healthy male Balb/c mice. Compounds displaying lung selective accumulation with good pharmacokinetic parameters will then be advanced to in vivo efficacy studies in Balb/c (nu/nu) mice bearing xenograft models of specific lung cancers. In the longer term, we will identify series of novel HDAC inhibitors that will be advanced to further preclinical/clinical evaluations. Additionally, the proposed studies will yield new insights on the roles of HDACs in the etiology of cancer. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer deaths in the US. Outlined in this proposal is a method that will enable identification of new classes of chemotherapeutic agents that possess lung- selective anti-cancer activity for targeted lung cancer therapy applications. Our proposed approach is expected to lead to chemotherapeutic agents with superior therapeutic indices and will significantly impact patient survival prognosis and positively contribute to human health management.