Bioinspired chemical probe approach targeting telomerase reverse transcriptase

项目摘要 端粒酶作为了解衰老过程和研究衰老机制的潜在靶点，已经引起了人们的极大关注。 癌症的治疗，因为端粒和端粒酶在转化中具有重要作用， 癌细胞的存活。以前流行的靶向端粒酶的策略是基于这样的假设： 在癌细胞中，端粒长度的维持是这种组装的唯一促生存功能。然而，在这方面， 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，B）端粒酶在关键细胞中的作用要大得多， 这些途径和功能还不清楚。尽管有一些有前途的临床候选人 在端粒酶抑制剂中，端粒酶靶向治疗在临床上的应用仍然是难以捉摸的， 令人沮丧的缓慢。这种缺乏进展的部分原因是， 端粒酶及其在癌症生物学中作用;值得注意的是，hTERT具有不同于 它的端粒延长活性与癌细胞存活有关。该提案建立在 Scheidt和Kron研究小组之间的合作，将我们在化学合成方面的专业知识， 癌症生物学承担围绕hTERT的知识的关键空白，其非典型功能， 参与癌细胞的存活。我们发现，基于天然产物的小分子 色乳霉素抑制端粒酶，并为探针开发提供独特的平台。基于鲁棒 化学和生物学的结果，我们建议首先开发增强的小分子探针， 功效这些化合物将使得能够精确共价修饰hTERT催化功能， 扰乱整个复杂的组件。以下目标将重点探讨这些新工具的使用 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器和细胞永生的决定因素的多种功能。长期 该项目的目标是了解和利用这些天然产物的分子基础， 分子工具影响端粒延长，最重要的是影响hTERT的非典型功能。 最终，这一新知识将推动对端粒酶及其活性的新认识的发展。 生物角色。

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.