Small Molecule Inhibitors of K13-Induced NF-kB Activation

K13 诱导的 NF-kB 激活的小分子抑制剂

• 批准号: 7554933
• 负责人: Preet M. Chaudhary
• 金额: $ 9.8万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7554933
• 关键词: Acquired Immunodeficiency Syndrome; Apoptosis; Biological; Biological Assay; Biological Process; CASP8 and FADD-like apoptosis regulating protein; Cell Line; Cell Proliferation; Cells; Complex; Development; Disease; Genome; Goals; Growth Factor; Herpesviridae; Human; Human Herpesvirus 8; Immunosuppression; Infection; Kaposi Sarcoma; Laboratories; Large-Cell Immunoblastic Lymphoma; Lead; Link; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Mediating; Morphologic artifacts; Multicentric Angiofollicular Lymphoid Hyperplasia; NF-kappa B; Names; Numbers; Oncogenes; Open Reading Frames; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Proteins; Reporter; Screening procedure; Testing; Therapeutic immunosuppression; Toxic effect; Viral; Viral Proteins; Virus; Virus Diseases; Withdrawal; assay development; base; caspase-8; chemotherapy; cytokine; effusion; high throughput screening; inhibitor/antagonist; metaplastic cell transformation; outcome forecast; promoter; small molecule

DESCRIPTION (provided by applicant): PROJECT SUMMARY Kaposi's sarcoma associated herpes virus (KSHV), also known as Human herpes virus 8 (HHV8), is the most frequent cause of malignancy among AIDS patients. Infection with KSHV has been linked to the occurrence of Kaposi's sarcoma (KS) and several lymphoproliferative disorders including primary effusion lymphoma (PEL), multicentric Castleman's disease and immunoblastic/plasmablastic lymphomas. Because of underlying immunosuppression, KSHV-associated cancers have extremely poor prognosis when treated with conventional chemotherapy and there is urgent need for more effective and less toxic therapies for these disorders. However, the exact mechanism of action of KSHV in the pathogenesis of these disorders is still unclear. We have discovered that K13, a KSHV-encoded vFLIP (viral FLICE inhibitory protein), possesses the unique abilities to activate the classical and alternative NF-?B pathways by interacting with different components of the I?B kinase (IKK) complex. We have further demonstrated that K13 is an oncogene that mediates increased cellular proliferation, transformation, cytokine secretion and protection against growth factor withdrawal-induced apoptosis via NF?B activation. Thus, we believe that K13 is a pivotal player in the pathogenesis of KSHV-associated lymphoproliferative disorders and an ideal candidate for development of molecularly targeted therapies. The primary goal of this proposal is to develop a high throughput assay to isolate small molecule inhibitors of K13-induced NF?B activation and test their ability to block its biological activities using assays established in our laboratory. We hope that these studies will not only lead to a better understanding of the various biological functions of K13 but also to the identification of less toxic and more effective molecularly targeted agents for the treatment of KSHV-associated cancers. PROJECT NARRATIVE Infection with the Kaposi's sarcoma associated herpesvirus (KSHV) has been linked to a number of human cancers. The goal of this project is to develop a screening assay to identify inhibitors of K13, a key protein encoded by this virus. Such inhibitors will lead to a better understanding of the K13 protein in the pathogenesis of KSHV-associated cancers and to the development of more effective drugs for their treatment.

描述（由申请人提供）：项目摘要Kaposi的肉瘤相关疱疹病毒（KSHV），也称为人类疱疹病毒8（HHV8），是艾滋病患者中最常见的恶性肿瘤原因。 KSHV的感染与Kaposi的肉瘤（KS）和几种淋巴增生性疾病有关，包括原发性积液淋巴瘤（PEL），多中心Castleman病和免疫母细胞/质质体淋巴瘤。由于潜在的免疫抑制，当接受常规化学疗法治疗时，KSHV相关的癌症的预后较差，并且迫切需要对这些疾病进行更有效且毒性较小的疗法。但是，KSHV在这些疾病发病机理中的确切作用机理尚不清楚。我们发现，K13是KSHV编码的VFLIP（病毒抑制蛋白），它具有通过与I？B激酶（IKK）复合物的不同成分相互作用来激活经典和替代NF-？B途径的独特能力。我们进一步证明，K13是一种癌基因，可介导细胞增殖，转化，细胞因子分泌和防止生长因子戒断诱导的凋亡通过NF？b激活的保护。因此，我们认为K13是KSHV相关淋巴增生性疾病的发病机理中的关键参与者，也是分子靶向疗法发展的理想候选者。该提案的主要目的是开发高吞吐量测定法，以分离K13诱导的NF？B激活的小分子抑制剂，并使用我们实验室中建立的测定法测试其阻断其生物活性的能力。我们希望这些研究不仅能够更好地了解K13的各种生物学功能，还可以鉴定毒性较小，靶向更有效的分子剂来治疗与KSHV相关的癌症的治疗。 Kaposi的肉瘤相关疱疹病毒（KSHV）的项目叙事感染与许多人类癌症有关。该项目的目的是开发筛选测定法，以鉴定K13的抑制剂，K13是该病毒编码的关键蛋白质。这种抑制剂将在与KSHV相关的癌症的发病机理中更好地了解K13蛋白，并开发出更有效的药物进行治疗。