Bioinspired chemical probe approach targeting telomerase reverse transcriptase

针对端粒酶逆转录酶的仿生化学探针方法

• 批准号: 10627813
• 负责人: Stephen J. Kron
• 金额: $ 37.83万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627813
• 关键词: Active Sites; Acute; Adult; Affect; Aging; American; Attention; Biological; Biological Assay; Buffers; CT26; Cancer Biology; Cancer Cell Growth; Catalytic Domain; Cell Aging; Cell Nucleus; Cell Proliferation; Cell Survival; Cell division; Cells; Cellular Stress; Chemicals; Chromosomes; Clinic; Collaborations; Colon Carcinoma; Complex; DNA Damage; DNA Double Strand Break; DNA Repair; DNA biosynthesis; Defect; Development; Diagnosis; Double Strand Break Repair; Evaluation; Experimental Neoplasms; Frustration; Generations; Genetic; Genetic Transcription; Goals; Growth; Hand; Human; Human Activities; Ionizing radiation; Knowledge; Length; Libraries; Link; Magic; Maintenance; Malignant Neoplasms; Methods; Mitochondria; Modeling; Modification; Molecular; Molecular Probes; Mus; Natural Products; Neoplasm Metastasis; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Process; Proliferating; RNA-Directed DNA Polymerase; Radiation; Radiation Induced DNA Damage; Radiation Tolerance; Radiation-Sensitizing Agents; Recurrence; Repetitive Sequence; Reporting; Repression; Research; Reverse Transcriptase Inhibitors; Role; Telomerase; Telomerase Inhibitor; Telomerase inhibition; Telomere Length Maintenance; Telomere Maintenance; Therapeutic; Tissues; Translating; Translations; Work; analog; cancer cell; cancer stem cell; cancer survival; cancer therapy; cell immortalization; cell transformation; chemical synthesis; clinical candidate; conventional therapy; design; early onset; genetic approach; genotoxicity; high reward; high risk; improved; inhibitor; insight; novel; pre-clinical; preservation; programs; response; senescence; small molecule; success; targeted treatment; telomere; tool; tumor; tumor progression; tumorigenesis; uncontrolled cell growth; Active Sites; Acute; Adult; Affect; Aging; American; Attention; Biological; Biological Assay; Buffers; CT26; Cancer Biology; Cancer Cell Growth; Catalytic Domain; Cell Aging; Cell Nucleus; Cell Proliferation; Cell Survival; Cell division; Cells; Cellular Stress; Chemicals; Chromosomes; Clinic; Collaborations; Colon Carcinoma; Complex; DNA Damage; DNA Double Strand Break; DNA Repair; DNA biosynthesis; Defect; Development; Diagnosis; Double Strand Break Repair; Evaluation; Experimental Neoplasms; Frustration; Generations; Genetic; Genetic Transcription; Goals; Growth; Hand; Human; Human Activities; Ionizing radiation; Knowledge; Length; Libraries; Link; Magic; Maintenance; Malignant Neoplasms; Methods; Mitochondria; Modeling; Modification; Molecular; Molecular Probes; Mus; Natural Products; Neoplasm Metastasis; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Process; Proliferating; RNA-Directed DNA Polymerase; Radiation; Radiation Induced DNA Damage; Radiation Tolerance; Radiation-Sensitizing Agents; Recurrence; Repetitive Sequence; Reporting; Repression; Research; Reverse Transcriptase Inhibitors; Role; Telomerase; Telomerase Inhibitor; Telomerase inhibition; Telomere Length Maintenance; Telomere Maintenance; Therapeutic; Tissues; Translating; Translations; Work; analog; cancer cell; cancer stem cell; cancer survival; cancer therapy; cell immortalization; cell transformation; chemical synthesis; clinical candidate; conventional therapy; design; early onset; genetic approach; genotoxicity; high reward; high risk; improved; inhibitor; insight; novel; pre-clinical; preservation; programs; response; senescence; small molecule; success; targeted treatment; telomere; tool; tumor; tumor progression; tumorigenesis; uncontrolled cell growth

PROJECT SUMMARY Telomerase has attracted significant attention as a potential target for understanding the aging process and for the treatment of cancer, since telomeres and telomerase have important roles in the transformation and survival of cancer cells. Previous prevailing strategies for targeting telomerase were based on the assumption that in cancer cells, telomere-length maintenance was the sole pro-survival function of this assembly. However, increasingly evidence strongly indicates that a) inhibition of the telomere-lengthening activity of telomerase is not a magic bullet treatment for cancer, and b) there is a much larger role for telomerase in key cellular pathways and these functions are not well understood. Although there have been promising clinical candidates among telomerase inhibitors, the translation of telomerase-targeted therapies to the clinic remains elusive and frustratingly slow. This lack of progress is due in part to the growing list of unanswered questions surrounding telomerase and its role in cancer biology; notably, that hTERT has non-canonical functions separate from its telomere-lengthening activity that are linked to cancer cell survival. This proposal builds on the collaboration between the Scheidt and Kron research groups to bring our expertise in chemical synthesis and cancer biology to bear on key gaps in the knowledge surrounding hTERT, its non-canonical functions, and its involvement in cancer cell survival. We have discovered that small molecules based on the natural product chrolactomycin inhibit telomerase and provide a unique platform for probe development. Based on robust chemical and biological results, we propose to first develop enhanced small molecule probes with improved efficacy. These compounds will enable precise covalent modification of hTERT catalytic function without perturbing the overall complex assembly. The following Aims will focus on exploring the use of these new tools to explore the role(s) of telomerase in DNA damage repair and cell senescence through in-depth analysis of multiple functions of telomerase as a buffer of cell stress and determinant of cell immortality. The long-term goal of this project is to understand and leverage the molecular basis for how these natural product-based molecular tools impact the telomere lengthening and most importantly, non-canonical functions of hTERT. Ultimately, this new knowledge will drive the development of new understanding of telomerase and its biological roles.

项目摘要 端粒酶已引起了重大关注，作为理解衰老过程和对的潜在目标 癌症的治疗，因为端粒和端粒酶在转化和 癌细胞的存活。以前的靶向端粒酶的盛行策略是基于假设 在癌细胞中，端粒长度的维持是该组装的唯一促生物性功能。然而， 越来越多的证据表明a）抑制端粒酶端粒延长活性为 不是对癌症的魔术子弹治疗，b）端粒酶在钥匙细胞中的作用要大得多 途径和这些功能尚未很好地理解。尽管有希望的临床候选人 在端粒酶抑制剂中，将端粒酶靶向疗法的翻译为诊所仍然难以捉摸，并且 令人沮丧的缓慢。缺乏进步的部分原因是围绕未解决的问题的列表越来越多 端粒酶及其在癌症生物学中的作用；值得注意的是，HTERT的非规范功能与 与癌细胞存活有关的端粒延长活性。该建议建立在 Scheidt和KRON研究小组之间的合作，以实现我们在化学合成方面的专业知识和 癌症生物学在围绕HTERT的知识，其非典型功能及其的知识中占有关键差距 参与癌细胞存活。我们已经发现基于天然产品的小分子 Chrolactomycin抑制端粒酶，并为探针开发提供独特的平台。基于强大的 化学和生物学效果，我们建议先开发增强的小分子探针，并有所改善 功效。这些化合物将实现HTERT催化功能的精确共价修改 扰动整体复合体组件。以下目标将重点探索这些新工具的使用 通过深入分析，探索端粒酶在DNA损伤修复和细胞衰老中的作用 端粒酶作为细胞应激的缓冲和细胞永生的决定因素的多个功能。长期 该项目的目标是了解和利用这些基于天然产品的分子基础 分子工具会影响端粒延长，最重要的是HTERT的非规范功能。 最终，这一新知识将推动对端粒酶及其其的新理解的发展 生物学作用。