Inhibitors of disease-promoting activities of senescence

衰老疾病促进活性的抑制剂

• 批准号: 7937488
• 负责人: Donald C. Porter
• 金额: $ 20万
• 依托单位: SENEX BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937488
• 关键词: Acute; Affect; Age; Aging; Alzheimer' s Disease; American; Animal Model; Apoptotic; Arthritis; Atherosclerosis; Binding; Biochemical; Biological; Biological Assay; Biotechnology; CDK2 gene; CDKN2A gene; Cell Aging; Cell Cycle; Cell Cycle Arrest; Cells; Cellular Assay; Chemicals; Chemoprevention; Chronic; Chronic Kidney Failure; Clinical Drug Development; Complex; Cyclin E; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Cyclins; Development; Disease; Drug Design; Enzymes; Family; Fibroblasts; Genes; Genetic Transcription; Goals; Growth; Human; Inhibitory Concentration 50; Lead; Malignant Neoplasms; Mediating; Modification; Molecular Target; Mus; Nude Mice; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phosphotransferases; Population; Post-Translational Protein Processing; Predisposition; Production; Protein Binding; Protein Family; Protein Secretion; Proteins; RNA Interference; Regulatory Pathway; Role; Series; Small Business Innovation Research Grant; Small Interfering RNA; Societies; Structure; Structure-Activity Relationship; Surveys; Testing; Therapeutic Uses; Toxic effect; Transcriptional Activation; Up-Regulation; age related; base; chemical synthesis; cytotoxic; design; drug discovery; efficacy testing; enzyme activity; improved; in vivo; inhibitor/antagonist; neoplastic cell; novel; oncoprotein p21; pre-clinical; prevent; programs; protein complex; prototype; public health relevance; response; senescence; small molecule; stoichiometry; tumor; tumor xenograft

DESCRIPTION (provided by applicant): This project is aimed at developing a new class of drugs, which act by inhibiting pathogenic activities of senescent cells. Cell senescence occurring as a result of aging or cellular damage, is associated with upregulation and secretion of proteins implicated in many age-related diseases, including cancer, Alzheimer's disease, atherosclerosis and arthritis. These proteins are induced in response to the expression of cell cycle inhibitors of cyclin-dependent kinase inhibitor (CKI) family, such as p21Waf1/Cip1 or p16Ink4A. Senex Biotechnology has identified a novel class of drug-like small molecules, SNX2-class compounds, which reduce the induction of disease-associated genes, senescence-associated morphological changes and secretion of tumor- promoting factors by CKI-arrested cells. Phase I studies of this project revealed that SNX2-class compounds affect CKI interaction with cyclin/CDK complexes in such a way that CDK2 kinase activity becomes much more susceptible to the inhibition by CKI, whereas transcriptional activation by CKI is greatly diminished. Thus SNX2-class compounds both prevent the upregulation of disease-associated proteins and enhance the tumor- suppressive activity of CKIs. The first aim of the Phase II program is to define the target of SNX2-class compounds at the biochemical level, as an approach to target-based design of drugs with the same activity. To test a hypothesis that SNX2-class compounds act by affecting post-translational modifications of the protein components of CKI/cyclin/CDK complexes, the component proteins will be analyzed for changes in their modifications upon treatment with SNX2-class compounds. Once the protein modifications susceptible to SNX2-class compounds are identified, the corresponding modifying enzymes will be tested as targets for inhibition by these compounds in cell-free assays. In another line of analysis, components of p21-containing protein complexes, the binding of which is affected by SNX2-class compounds, will be identified. The potential role of such proteins in CKI-induced transcription will be tested by RNA interference assays. The second aim of the program is to carry out chemical optimization and structure-activity analysis of lead compounds of SNX2 family. The optimization strategy, based on the activity of 40 SNX2-related compounds, will guide the synthesis of chemical derivatives, which will be tested for efficacy in preventing the induction of transcription by p21 and for their effect on the target enzyme activity, as identified in the first aim. These assays will elucidate the structure-activity relationship of SNX2 family proteins for designing more efficacious compounds of the same family. The third aim of the program is to test lead compounds of SNX2 family for acute toxicity in mice and for ex vivo and in vivo efficacy in inhibiting the tumor-promoting activity of senescent fibroblasts. These studies will provide an in vivo proof-of-principle for therapeutic use of SNX2-class compounds. Successful completion of Phase II will allow us to generate strategies and candidate compounds for preclinical and clinical development of drugs with a novel mechanism of action and with broad applicability to cancer and Alzheimer's disease. PUBLIC HEALTH RELEVANCE: With the aging of the American population, chronic age-related diseases, such as Alzheimer's disease, atherosclerosis, chronic renal disease and cancer, are becoming an increasingly greater burden on the society. There is a great need for developing novel pharmaceuticals that would be efficient against these largely incurable diseases. Senex Biotechnology, Inc. is a small drug discovery company that targets a newly discovered biological regulatory pathway, which causes increased production of proteins implicated in many age-related diseases. Senex has discovered prototype drug-like small molecules that block this disease- promoting pathway. The goal of this Phase II SBIR application is to identify the molecular target of these compounds, increase their biological activity and demonstrate their efficacy in an animal model. These studies will make it possible to develop this new class of molecules as potential drugs against the diseases of old age, including cancer and Alzheimer's disease.

描述（由申请人提供）：该项目旨在开发一种新的药物，该药物通过抑制衰老细胞的致病活性来起作用。衰老或细胞损伤导致的细胞衰老与许多与年龄相关疾病有关的蛋白质的上调和分泌有关，包括癌症，阿尔茨海默氏病，动脉粥样硬化和关节炎。这些蛋白是响应细胞周期依赖性激酶抑制剂（CKI）家族的细胞周期抑制剂的表达而诱导的，例如P21WAF1/CIP1或P16INK4A。 Senex Biotechnology已经确定了一种新型的药物样小分子，SNX2级化合物，可减少与疾病相关基因的诱导，衰老相关的形态变化和CKI降落细胞对肿瘤促进因子的分泌。对该项目的第一阶段研究表明，SNX2级化合物会影响CKI与细胞周期蛋白/CDK复合物的相互作用，以至于CDK2激酶的活性变得更容易受到CKI抑制的影响，而CKI的转录激活却大大减少了。因此，SNX2级化合物既可以防止疾病相关蛋白的上调，又可以增强CKI的肿瘤抑制活性。 II期计划的第一个目的是定义生物化学水平上SNX2级化合物的靶标，作为一种具有相同活性的基于目标的药物设计的方法。为了检验一个假设，即SNX2级化合物通过影响CKI/Cyclin/CDK络合物的蛋白质成分的翻译后修饰作用，将分析成分蛋白，以分析使用SNX2级化合物治疗后修饰后的变化。一旦鉴定出易受SNX2类化合物的蛋白质修饰，相应的修饰酶将被测试作为这些化合物在无细胞测定中抑制的靶标。在另一条分析中，将鉴定出含P21的蛋白质复合物的成分，其结合受SNX2级化合物的影响。这种蛋白质在CKI诱导的转录中的潜在作用将通过RNA干扰测定测试。该计划的第二个目的是对SNX2家族的铅化合物进行化学优化和结构活性分析。基于40种与SNX2相关化合物的活性的优化策略将指导化学衍生物的合成，该化学衍生物将在第一个目标中确定的疗效在防止p21诱导转录的功效以及它们对目标酶活性的影响。这些测定法将阐明SNX2家族蛋白的结构活性关系，以设计同一家族的更有效化合物。该程序的第三个目的是测试SNX2家族的铅化合物，以在小鼠，离体和体内抑制衰老成纤维细胞肿瘤促进活性方面的急性毒性。这些研究将为SNX2级化合物的治疗使用提供体内原则证明。成功完成II期将使我们能够生成具有新颖的作用机理以及对癌症和阿尔茨海默氏病的广泛适用性的临床前和临床开发的策略和候选化合物。公共卫生相关性：随着美国人群的老龄化，与慢性年龄相关的疾病，例如阿尔茨海默氏病，动脉粥样硬化，慢性肾脏疾病和癌症，正在成为社会越来越大的负担。非常需要开发新型药物，这些药物将有效地针对这些基本无法治愈的疾病。 Senex Biotechnology，Inc。是一家针对新发现的生物调节途径的小型药物发现公司，该途径会导致与许多年龄相关疾病有关的蛋白质产生增加。塞内克斯（Senex）发现了原型药物样的小分子，可以阻止这种疾病促进途径。该II期SBIR应用的目的是确定这些化合物的分子靶标，增加其生物学活性并在动物模型中证明其功效。这些研究将有可能开发这种新的分子作为针对老年疾病的潜在药物，包括癌症和阿尔茨海默氏病。