Bioinspired chemical probe approach targeting telomerase reverse transcriptase

项目总结 端粒酶作为一个潜在的靶点已经引起了人们的广泛关注，以了解衰老过程和 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，端粒长度的维持是该组件唯一的促生存功能。然而， 越来越多的证据表明，a)端粒延长活性的抑制是 不是治疗癌症的灵丹妙药，以及b)端粒酶在关键细胞中发挥着更大的作用 这些途径和这些功能还没有被很好地理解。尽管已经有一些很有前途的临床候选人 在端粒酶抑制剂中，端粒酶靶向治疗的临床应用仍然难以捉摸。 慢得令人沮丧。这种缺乏进展的部分原因是围绕着越来越多的悬而未决的问题 端粒酶及其在癌症生物学中作用；值得注意的是，hTERT具有独立于 它的端粒延长活性与癌细胞的存活有关。这项建议建立在 Scheidt和Kron研究小组之间的合作，将我们在化学合成和 癌症生物学将填补围绕hTERT的关键知识空白，它的非规范功能，以及 参与癌细胞的存活。我们已经发现，基于天然产物的小分子 氯霉素抑制端粒酶，为探针开发提供独特的平台。基于健壮性 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。这些化合物将使hTERT催化功能的精确共价修饰成为可能，而无需 扰乱了整个复杂的装配。以下目标将侧重于探索这些新工具的使用 通过对端粒酶的深入分析，探讨端粒酶在DNA损伤修复和细胞衰老中的作用(S) 端粒酶作为细胞应激的缓冲和细胞永生的决定因素具有多种功能。长期的 这个项目的目标是理解和利用分子基础，了解这些天然产品是如何 分子工具影响端粒的延长，最重要的是，影响hTERT的非规范功能。 最终，这一新知识将推动对端粒酶及其基因的新理解的发展 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.