A High Throughput Protein Complementation Assay for Inhibitors of NEMO-K13 Intera

NEMO-K13 Intera 抑制剂的高通量蛋白质互补测定

基本信息

批准号：
8296061
负责人：
Preet M. Chaudhary
金额：
$ 26.09万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8296061
关键词：
Acquired Immunodeficiency Syndrome Apoptosis Biological Biological Assay Biological Process CASP8 and FADD-like apoptosis regulating protein CASP8 gene Cell Line Cell Proliferation Cells Clinical Complex Development Disease Firefly Luciferases Genome Goals Growth Factor HIV Human Human Herpesvirus 8 Hydrocarbons Immune response Immunocompromised Host Immunosuppression Immunotherapy Infection Inflammatory Response Jurkat Cells Kaposi Sarcoma Large-Cell Immunoblastic Lymphoma Lead Link Luciferases Lymphoma Lymphoproliferative Disorders Malignant Neoplasms Molecular Morphologic artifacts Multicentric Angiofollicular Lymphoid Hyperplasia NF-kappa B Names Non-Hodgkin&apos s Lymphoma Open Reading Frames Pathogenesis Pathway interactions Patients Peptides Phosphotransferases Physiological Play Protein Fragment Proteins Regimen Reporter Reproducibility Screening procedure Solid Subgroup Testing Toxic effect Viral Viral Proteins Withdrawal base caspase-8 cytokine domain mapping drug development effusion genetic regulatory protein high throughput screening inhibitor/antagonist metaplastic cell transformation novel outcome forecast public health relevance reconstitution small molecule therapeutic target young adult

项目摘要

DESCRIPTION (provided by applicant): Human Herpesvirus 8 (HHV8, also known as KSHV) is one of the commonest causes of malignancies among young adults in parts of the world and has been associated with Kaposi's sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). The prognosis of patients with HHV8-associated lymphoproliferative disorders is extremely poor due to their immunocompromised status and there is an urgent need for less toxic therapies for the treatment of these malignancies. We have discovered that K13, a small protein encoded by HHV8, directly interacts with the NEMO/IKK3 subunit of the IkB kinase (IKK) complex to activate the NF-kB pathway and utilizes this pathway to promote cellular survival, proliferation, transformation and cytokine secretion. The above studies have established NF-kB pathway as an important therapeutic target for the treatment of HHV8-associated malignancies. However, since NF-kB pathway plays a key role in normal immune and inflammatory response, global inhibitors of this pathway are likely to lead to severe immunosuppression, thus limiting their potential clinical utility in HHV8-infected patients. To circumvent this problem, we propose to develop a high throughput screening (HTS) assay for isolating small molecule inhibitors of K13-NEMO interaction. It is hoped that such inhibitors will specifically block K13-induced NF-kB without interfering with the physiological activation of this pathway during normal immune and inflammatory response. Furthermore, specific inhibitors of K13-NEMO interaction will serve as useful pharmacological probes to understand the various biological activities of K13. PUBLIC HEALTH RELEVANCE: Infection with the Human Herpesvirus 8 (HHV8) has been linked to a number of human cancers. In this project, we propose to develop a high throughput screening assay for compounds that can block the interaction of K13, a small protein encoded by HHV8, with the cellular regulatory protein NEMO. It is hoped that such compounds will not only lead to a better understanding of the biological functions of K13 but also serve as lead compounds for the development of targeted therapies for HHV8-associated malignancies.

描述（由申请人提供）：人类疱疹病毒8（HHV8，也称为KSHV）是世界各地的年轻人中最常见的恶性肿瘤原因之一，并且与Kaposi的肉瘤，一级积液淋巴瘤（PEL）和多中心有关Castleman病（MCD）。 HHV8相关的淋巴增生性疾病的预后由于其免疫功能低下的状态非常差，并且迫切需要减少毒性疗法来治疗这些恶性肿瘤。我们发现，由HHV8编码的小蛋白K13直接与IKB激酶（IKK）复合物的Nemo/ikk3亚基相互作用，以激活NF-KB途径，并利用此途径来促进细胞存活，增殖，转化和细胞质，并促进细胞存活，转化和细胞质？分泌。上述研究已将NF-KB途径建立为治疗与HHV8相关的恶性肿瘤的重要治疗靶点。但是，由于NF-KB途径在正常免疫和炎症反应中起关键作用，因此该途径的全球抑制剂可能会导致严重的免疫抑制，从而限制了其在HHV8感染患者中的潜在临床效用。为了解决这个问题，我们建议开发高吞吐量筛选（HTS）测定法，以分离K13-NEMO相互作用的小分子抑制剂。希望这种抑制剂能特异性地阻断K13诱导的NF-KB，而不会在正常的免疫和炎症反应期间干扰该途径的生理激活。此外，K13-NEMO相互作用的特定抑制剂将作为了解K13的各种生物学活性的有用药理探针。公共卫生相关性：与人类疱疹病毒8（HHV8）的感染与许多人类癌症有关。在这个项目中，我们建议对可以阻止K13相互作用的化合物进行高吞吐量筛选测定法，该化合物是由HHV8编码的小蛋白质与细胞调节蛋白Nemo的相互作用。希望这种化合物不仅能够更好地了解K13的生物学功能，而且还可以作为开发HHV8相关恶性肿瘤的靶向疗法的铅化合物。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors.

DOI：
10.1038/onc.2013.242
发表时间：
2014-05-29
期刊：
Oncogene
影响因子：
8
作者：
Tolani B;Gopalakrishnan R;Punj V;Matta H;Chaudhary PM
通讯作者：
Chaudhary PM

A purine scaffold HSP90 inhibitor BIIB021 has selective activity against KSHV-associated primary effusion lymphoma and blocks vFLIP K13-induced NF-κB.

DOI：
10.1158/1078-0432.ccr-12-3510
发表时间：
2013-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Gopalakrishnan R;Matta H;Chaudhary PM
通讯作者：
Chaudhary PM

A computational profiling of changes in gene expression and transcription factors induced by vFLIP K13 in primary effusion lymphoma.