Inhibitors of disease-promoting activities of senescence

衰老疾病促进活性的抑制剂

• 批准号: 7612454
• 负责人: Donald C. Porter
• 金额: $ 61.15万
• 依托单位: SENEX BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612454
• 关键词: Acute; Affect; Age; Aging; Alzheimer' s Disease; American; Animal Model; Apoptotic; Arthritis; Atherosclerosis; Binding; Biochemical; Biological; Biological Assay; Biotechnology; CDK2 gene; CDKN1A gene; CDKN2A gene; Cell Aging; Cell Cycle; Cell Cycle Arrest; Cells; Cellular Assay; Chemicals; Chemoprevention; Chronic; Chronic Kidney Failure; Class; 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; Public Health; RNA Interference; Regulatory Pathway; Role; Series; Small Business Funding Mechanisms; 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; enzyme activity; improved; in vivo; inhibitor/antagonist; neoplastic cell; novel; oncoprotein p21; pre-clinical; prevent; programs; prototype; 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）：该项目旨在开发一类新型药物，其通过抑制衰老细胞的致病活性发挥作用。由于衰老或细胞损伤而发生的细胞衰老与许多与年龄相关的疾病（包括癌症、阿尔茨海默病、动脉粥样硬化和关节炎）中涉及的蛋白质的上调和分泌有关。这些蛋白是响应细胞周期蛋白依赖性激酶抑制剂 (CKI) 家族的细胞周期抑制剂（例如 p21Waf1/Cip1 或 p16Ink4A）的表达而诱导的。 Senex Biotechnology 已经鉴定出一类新型药物样小分子，即 SNX2 类化合物，它可以减少 CKI 阻滞细胞对疾病相关基因的诱导、衰老相关的形态变化以及肿瘤促进因子的分泌。该项目的第一阶段研究表明，SNX2 类化合物影响 CKI 与细胞周期蛋白/CDK 复合物的相互作用，从而使 CDK2 激酶活性变得更容易受到 CKI 的抑制，而 CKI 的转录激活则大大减弱。因此，SNX2 类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期计划的首要目标是在生化水平上定义SNX2类化合物的靶点，作为基于靶点设计具有相同活性的药物的方法。为了检验 SNX2 类化合物通过影响 CKI/细胞周期蛋白/CDK 复合物的蛋白质成分的翻译后修饰而发挥作用的假设，将分析这些成分蛋白质在用 SNX2 类化合物处理后其修饰的变化。一旦鉴定出对 SNX2 类化合物敏感的蛋白质修饰，相应的修饰酶将作为这些化合物在无细胞测定中抑制的靶标进行测试。在另一条分析中，将鉴定含有 p21 的蛋白质复合物的成分，其结合受到 SNX2 类化合物的影响。这些蛋白质在 CKI 诱导转录中的潜在作用将通过 RNA 干扰测定进行测试。该项目的第二个目标是对SNX2家族先导化合物进行化学优化和构效分析。该优化策略基于 40 种 SNX2 相关化合物的活性，将指导化学衍生物的合成，并将测试其在防止 p21 诱导转录方面的功效及其对目标酶活性的影响，如第一个目标。这些测定将阐明 SNX2 家族蛋白的结构-活性关系，以设计同一家族的更有效的化合物。该计划的第三个目标是测试 SNX2 家族的先导化合物对小鼠的急性毒性以及抑制衰老成纤维细胞的肿瘤促进活性的离体和体内功效。这些研究将为 SNX2 类化合物的治疗用途提供体内原理验证。第二阶段的成功完成将使我们能够为药物的临床前和临床开发制定策略和候选化合物，这些药物具有新颖的作用机制，并且广泛适用于癌症和阿尔茨海默病。公共健康相关性：随着美国人口老龄化，阿尔茨海默氏病、动脉粥样硬化、慢性肾病和癌症等与年龄相关的慢性疾病正在成为越来越大的社会负担。非常需要开发能够有效对抗这些基本上无法治愈的疾病的新型药物。 Senex Biotechnology, Inc. 是一家小型药物发现公司，其目标是新发现的生物调节途径，该途径会导致与许多年龄相关疾病有关的蛋白质产量增加。 Senex 发现了原型药物小分子，可以阻断这种促进疾病的途径。 II 期 SBIR 应用的目标是确定这些化合物的分子靶标，提高其生物活性并在动物模型中证明其功效。这些研究将使开发这类新型分子作为治疗老年疾病（包括癌症和阿尔茨海默病）的潜在药物成为可能。