HDAC6-Selective Inhibitors for Pancreatic Cancer Treatment

用于胰腺癌治疗的 HDAC6 选择性抑制剂

• 批准号: 7689170
• 负责人: WERNER TUECKMANTEL
• 金额: $ 1.24万
• 依托单位: PSYCHOGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-18 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689170
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Acetylation; Apoptosis; Area; Biological; Cancer Cell Growth; Cancer Etiology; Cancer cell line; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cell Survival; Cessation of life; Checkpoint kinase 1; Chemicals; Client; Clinical Research; DNA Damage; DNA damage checkpoint; Data; Development; Disease; Epidermal Growth Factor Receptor; Epigenetic Process; Euchromatin; Event; Excision; Funding; Gelsolin; Gene Expression; Growth; Growth Factor; HDAC3 gene; HDAC6 gene; Heat-Shock Proteins 90; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; In Vitro; Incidence; Induction of Apoptosis; Isoenzymes; Lead; Learning; Left; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Modification; Molecular Biology; Mus; Mutagens; Mutation; Nature; Normal Cell; Oncogenic; Operative Surgical Procedures; Patients; Phase; Post-Translational Protein Processing; Protein Acetylation; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; Safety; Series; Structure-Activity Relationship; TP53 gene; Testing; Therapeutic; Therapeutic Agents; Tumor Cell Line; Tumor Suppressor Genes; United States; Up-Regulation; Vorinostat; Work; Xenograft procedure; alternative treatment; analog; angiogenesis; cancer cell; cancer therapy; cell growth; chemotherapeutic agent; chemotherapy; conventional therapy; gemcitabine; histone acetyltransferase; improved; in vivo; inhibitor/antagonist; insight; mortality; neoplastic cell; novel; novel therapeutics; overexpression; pancreatic neoplasm; professor; public health relevance; research study; tumorigenic

DESCRIPTION (provided by applicant): Pancreatic cancer is the fifth leading cause of cancer death in the US. Despite tremendous efforts aimed at understanding its molecular biology, conventional treatment has had little impact. Due to the highly metastatic nature of the disease, surgery is available to only 15- 20% of patients. Thus, the development and characterization of new therapeutic agents that can be used alone or together with conventional therapies is desperately needed. There are 4 classes of HDACs, and it is hypothesized that increased HDAC activity in cancer cells may contribute to the epigenetic silencing of tumor suppressor genes such as p16, p21 and gelsolin. In fact, treatment of pancreatic cancer cells with the broad spectrum classI/II HDAC inhibitor (HDACI), SAHA, leads to upregulation of p21, growth inhibition and induction of apoptosis. The team of Professor Kozikowski at UIC has recently generated novel classes of HDACIs, several of which show low pM activity toward HDAC6 and HDAC3 in vitro. Treatment of pancreatic cancer cells with these compounds results in a G1 and/or G2 arrest and induction of apoptosis. In addition, the data indicate that some of these novel HDACIs cause loss of the DNA damage checkpoint kinase, Chk1. It is hypothesized that they can sensitize pancreatic tumor cells to genotoxic agents. We believe that a combination of these HDACIs with DNA damage-inducing agents, such as gemcitabine, will provide significant therapeutic benefit compared to the conventional treatment, gemcitabine alone. To test this hypothesis, we propose to (1) re-synthesize the 12 most active HDACIs made at UIC, and to synthesize 10 new analogs and test them for isoform selectivity; (2) to define biological effects of HDACIs on pancreatic tumor cell proliferation and survival in vitro; and (3) to determine the in vivo efficacy of the 5 best HDACIs on established pancreatic tumor cell line xenografts with co-administration of gemcitabine. These studies will provide important information regarding the use of HDACIs in combination with therapeutic agents that cause DNA damage, and valuable structure-activity relationship (SAR) data relevant to the safety and efficacy of these compounds in the treatment of pancreatic cancer, while allowing to gauge the extent to which isoform selectivity is required in finding a "safe" therapy. The biological characterization of the HDACIs presented herein may also allow to better link specific isoforms to tumorigenic events. The two or three best HDACIs identified in this Phase I proposal will be the subject of a Phase II application to fund ADMET work aimed at advancing one of these compounds into clinical studies. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fifth leading cause of cancer death in the US and is poorly treatable by conventional chemotherapy, while surgery is available to only 15-20% of patients due to the highly metastatic nature of the disease. The present application aims at investigating the ability of a novel series of inhibitors of histone deacetylases (HDACs), which have been shown to inhibit pancreatic cancer cell growth in vitro and lead to apoptosis, to inhibit the growth of pancreatic tumor cell line xenografts in mice in combination with the conventional chemotherapeutic agent, gemcitabine. Positive results would lead to a Phase II application to fund ADMET work aimed at advancing one of these compounds into clinical studies.

描述（由申请人提供）：胰腺癌是美国癌症死亡的第五大原因。尽管为了解其分子生物学做出了巨大努力，但常规治疗几乎没有影响。由于该疾病的高度转移性，只有15- 20%的患者可以进行手术。因此，迫切需要开发和表征可单独使用或与常规疗法一起使用的新治疗剂。有4类HDAC，并且假设癌细胞中HDAC活性的增加可能有助于肿瘤抑制基因如p16、p21和凝溶胶蛋白的表观遗传沉默。事实上，用广谱I/II类HDAC抑制剂（HDACI）SAHA治疗胰腺癌细胞导致p21上调、生长抑制和细胞凋亡诱导。UIC的Kozikowski教授的团队最近产生了新型HDACIs，其中几种在体外对HDAC 6和HDAC 3表现出低pM活性。用这些化合物处理胰腺癌细胞导致G1和/或G2停滞和诱导细胞凋亡。此外，数据表明，这些新型HDACI中的一些导致DNA损伤检查点激酶Chk 1的丢失。据推测，它们可以使胰腺肿瘤细胞对遗传毒性剂敏感。我们认为，与常规治疗（单独使用吉西他滨）相比，这些HDACI与DNA损伤诱导剂（如吉西他滨）的组合将提供显著的治疗益处。为了验证这一假设，我们提出：（1）重新合成UIC生产的12种最具活性的HDACIs，并合成10种新的类似物，并测试它们的异构体选择性;（2）确定HDACIs对胰腺肿瘤细胞增殖和存活的体外生物学效应;和（3）确定5种最佳HDACI与吉西他滨共同给药对已建立的胰腺肿瘤细胞系异种移植物的体内功效。这些研究将提供关于HDACI与引起DNA损伤的治疗剂组合使用的重要信息，以及与这些化合物在胰腺癌治疗中的安全性和有效性相关的有价值的结构-活性关系（SAR）数据，同时允许测量在寻找“安全”疗法中需要的异构体选择性的程度。本文提供的HDACI的生物学表征还可以允许更好地将特异性同种型与致瘤事件联系起来。在第一阶段提案中确定的两个或三个最好的HDACI将成为第二阶段申请的主题，以资助ADMET工作，旨在将这些化合物之一推进临床研究。 公共卫生关系：胰腺癌是美国癌症死亡的第五大原因，并且通过常规化疗治疗效果不佳，而由于该疾病的高度转移性，仅15-20%的患者可进行手术。本申请旨在研究组蛋白脱乙酰酶（HDAC）的新系列抑制剂与常规化疗剂吉西他滨组合抑制小鼠中胰腺肿瘤细胞系异种移植物生长的能力，所述HDAC已显示在体外抑制胰腺癌细胞生长并导致细胞凋亡。积极的结果将导致第二阶段的申请，以资助ADMET工作，旨在推进这些化合物之一进入临床研究。