Ubiquitin based therapy of aggressive cancer cell populations

基于泛素的侵袭性癌细胞群治疗

基本信息

批准号：
8777725
负责人：
David E Sterner
金额：
$ 22.48万
依托单位：
PROGENRA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-07 至 2016-07-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8777725
关键词：
Antineoplastic Agents Apoptotic Applications Grants Area Bacteria Biochemical Biological Assay Bortezomib Breast Cancer Model Cell model Cells Cellular Assay Cessation of life Cleaved cell Clinical Clinical Trials Colorectal Colorectal Cancer Complex Development Disease Enzymes Excision Exhibits Gene Targeting Genes Genetic Transcription Goals Growth Histone Deacetylase Human Incidence Lead Length Lung Malignant Neoplasms Malignant neoplasm of prostate Modeling Multienzyme Complexes Multiple Myeloma Multiprotein Complexes Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenes Pathway interactions Peptide Hydrolases Performance Pharmaceutical Chemistry Pharmacodynamics Phase Population Post-Translational Protein Processing Proteasome Inhibitor Proteins Refractory Reporting Resistance SAGA Series Sum System Testing Ubiquitin Ubiquitin family Work aggressive therapy anticancer activity base cancer cell cofactor combat cyclin D2 drug discovery experience high throughput screening in vivo in vivo Model inhibitor/antagonist interest member mouth squamous cell carcinoma multicatalytic endopeptidase complex neoplastic novel overexpression pre-clinical public health relevance research study screening small molecule small molecule libraries success tumor tumor progression ubiquitin-protein ligase

Antineoplastic Agents Apoptotic Applications Grants Area Bacteria Biochemical Biological Assay Bortezomib Breast Cancer Model Cell model Cells Cellular Assay Cessation of life Cleaved cell Clinical Clinical Trials Colorectal Colorectal Cancer Complex Development Disease Enzymes Excision Exhibits Gene Targeting Genes Genetic Transcription Goals Growth Histone Deacetylase Human Incidence Lead Length Lung Malignant Neoplasms Malignant neoplasm of prostate Modeling Multienzyme Complexes Multiple Myeloma Multiprotein Complexes Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenes Pathway interactions Peptide Hydrolases Performance Pharmaceutical Chemistry Pharmacodynamics Phase Population Post-Translational Protein Processing Proteasome Inhibitor Proteins Refractory Reporting Resistance SAGA Series Sum System Testing Ubiquitin Ubiquitin family Work aggressive therapy anticancer activity base cancer cell cofactor combat cyclin D2 drug discovery experience high throughput screening in vivo in vivo Model inhibitor/antagonist interest member mouth squamous cell carcinoma multicatalytic endopeptidase complex neoplastic novel overexpression pre-clinical public health relevance research study screening small molecule small molecule libraries success tumor tumor progression ubiquitin-protein ligase

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项目摘要

DESCRIPTION (provided by applicant): The degradation of most cellular proteins is regulated by coordinated addition and removal of ubiquitin by families of ubiquitin E3 ligases and deubiquitylating enzymes (DUBs) respectively. DUBs proteolytically cleave ubiquitin molecules from proteins resulting in modifications of protein activity, localization and function. Several DUBs are aberrantly regulated in cancer, including the best studied, USP7, selective inhibitors of which are active in cancer models. A second DUB, USP22, is another validated anticancer target, being one of 11 genes in the death-from-cancer gene signature, a component of the human SAGA transcriptional cofactor complex regulating myc transcription, and a regulator of the expression of p21, the histone deacetylase Sirt 1, and p53 activity. USP22 is overexpressed in oral squamous cell carcinoma, breast, non-small cell lung, colorectal, and other cancers and its expression is inversely correlated with survival. Unlike most other DUBs, USP22 exhibits robust activity only as a component of a multi-subunit complex. Initial studies reported activity solely as a member of the 2MDa SAGA complex, but more recently it has been demonstrated that USP22 exhibits similar activity in a four-protein DUB module derived from the SAGA complex. Based on Progenra's success working with DUB complexes, it is proposed here to develop a HTS compliant assay to enable the identification of novel inhibitors of USP22. Following a screen of Progenra's 200K member diversity based library of small molecules, compounds of interest will be characterized further against a panel of DUBs and other proteases and cellular activity will be explored by testing the modulation of a series of well validated pharmacodynamic markers. The primary goal is to identify novel inhibitors of USP22; specific milestones include: purification of active USP22 DUB complex, configuration of an HTS compliant USP22 assay format and identification of selective USP22 inhibitors with activity in cellular models. The most interesting compounds will be advanced, in Phase II, to hit-to-lead medicinal chemistry optimization with associated DMPK and in vivo activity.

描述（由申请人提供）：大多数细胞蛋白的降解通过分别由泛素E3连接酶和去偶联酶（DUB）的家族协调添加和去除泛素来调节。蛋白质分裂的蛋白质分子从蛋白质上裂解，导致蛋白质活性，定位和功能的改变。在癌症中，几个配音受到异常调节，包括研究最佳的USP7，有选择性抑制剂在癌症模型中活跃。第二个配音USP22是另一个经过验证的抗癌靶标，是死亡中癌基因签名的11个基因之一，是调节MYC转录的人类传染性转录辅因子复合物的成分，是p21的调节剂，p21的调节剂，组蛋白脱乙酰酶Sirt sirt sirt sirt sirt sirt sirt sirt 1和p53活性。 USP22在口服鳞状细胞癌，乳腺癌，非小细胞肺，结直肠癌和其他癌症中过表达，其表达与存活率成反比。与大多数其他DUB不同，USP22仅作为多种亚基复合物的组成部分表现出鲁棒的活动。初步研究报告的活动仅是2MDA传奇复合物的成员，但最近已证明USP22在源自SAGA复合物的四蛋白DUB模块中表现出相似的活性。基于后代与DUB复合物的成功，这里提议开发符合HTS的测定法，以鉴定USP22的新型抑制剂。遵循后代基于200k成员多样性的小分子库的屏幕，将通过测试一系列经过良好验证的药态动力学标记的调制来探索感兴趣的化合物和其他蛋白酶和其他蛋白酶和细胞活性的进一步表征。主要目标是确定USP22的新型抑制剂；特定的里程碑包括：纯化主动USP22 DUB复合物，符合HTS的USP22测定格式的配置以及在细胞模型中具有活性的选择性USP22抑制剂的鉴定。在II期中，最有趣的化合物将采用与相关的DMPK和体内活性进行铅对铅化学优化。