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: 10411995
• 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/10411995
• 关键词: Active Sites; Acute; Address; 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; Generations; Genetic; Genetic Transcription; Goals; Growth; Hand; Human; 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; RNA-Directed DNA Polymerase; Radiation; Radiation Induced DNA Damage; Radiation Tolerance; Radiation-Sensitizing Agents; Recurrence; Repetitive Sequence; Reporting; Research; Role; Telomerase; Telomerase Inhibitor; Telomere Length Maintenance; Telomere Maintenance; Therapeutic; Tissues; Translating; Translations; Ursidae Family; Work; analog; base; cancer cell; cancer stem cell; cancer survival; cancer therapy; 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.

项目概要 端粒酶作为了解衰老过程和促进衰老的潜在靶标而引起了广泛关注。 端粒和端粒酶在癌症的转化和治疗中具有重要作用 癌细胞的存活。以前针对端粒酶的流行策略基于以下假设 在癌细胞中，端粒长度的维持是该组装体唯一的促生存功能。然而， 越来越多的证据有力地表明，a) 抑制端粒酶的端粒延长活性 不是治疗癌症的灵丹妙药，而且 b) 端粒酶在关键细胞中发挥着更大的作用 途径和这些功能尚不清楚。尽管已经出现了有希望的临床候选药物 在端粒酶抑制剂中，端粒酶靶向疗法向临床的转化仍然难以捉摸， 慢得令人沮丧。缺乏进展的部分原因是围绕以下问题的未解答问题越来越多 端粒酶及其在癌症生物学中的作用；值得注意的是，hTERT 具有与 它的端粒延长活性与癌细胞的存活有关。该提案建立在 Scheidt 和 Kron 研究小组之间的合作，将我们在化学合成和 癌症生物学填补了有关 hTERT、其非规范功能及其相关知识的关键空白 参与癌细胞的存活。我们发现基于天然产物的小分子 色拉霉素抑制端粒酶并为探针开发提供独特的平台。基于稳健的 根据化学和生物学结果，我们建议首先开发具有改进的增强型小分子探针 功效。这些化合物将能够精确共价修饰 hTERT 催化功能，而无需 扰乱整个复杂的装配体。以下目标将重点探索这些新工具的使用 通过深入分析端粒酶在 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剂和细胞永生的决定因素的多种功能。长期来看 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 分子工具影响端粒延长，最重要的是影响 hTERT 的非规范功能。 最终，这些新知识将推动对端粒酶及其作用的新理解的发展 生物学作用。