Chemical Proteomic Platforms for Radically Expanding Cancer Druggability

用于从根本上扩展癌症成药性的化学蛋白质组学平台

• 批准号: 10477261
• 负责人: BENJAMIN F CRAVATT
• 金额: $ 113.78万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477261
• 关键词: Basic Science; Biological Response Modifier Therapy; Biology; Cells; Chemicals; Code; DNA sequencing; Development; Future; Goals; Human; Human Genetics; Immune; Immunology; Immunooncology; Knowledge; Malignant Neoplasms; Maps; Medicine; Methods; Modernization; Molecular; Mutate; Natural Immunity; Oncogenes; Pharmacology; Play; Proteins; Proteome; Proteomics; Research; Role; System; Technology; Therapeutic; Translating; Translational Research; Validation; activity-based protein profiling; adaptive immunity; anticancer research; biological systems; cancer cell; cancer therapy; gene discovery; genetic information; innovation; insight; novel therapeutics; programs; protein degradation; small molecule; small molecule libraries; tumor immunology; tumorigenesis; ubiquitin-protein ligase

Cancer research and treatment have greatly benefited from advances in DNA sequencing methods, which have accelerated the discovery of genes that, when mutated, promote tumorigenesis. The protein products of some of these oncogenes have served as direct targets for groundbreaking new medicines. Many oncogenes, however, code for proteins that lack chemical probes and are even considered undruggable. In these cases, our understanding of the molecular basis of cancer has not yet translated into effective new therapies. A similar gap can be found in cancer-related immunology (or immuno-oncology), where human genetics is discovering proteins that play fundamental roles in innate and adaptive immunity; yet, again, most of these proteins lack chemical probes. A critical challenge has thus emerged in cancer research – how can the massive gains in understanding of cancer and immunology bequeathed by modern human genetics be translated into new therapies for cancer? The goal of this research program is to leverage and extend our lab’s innovative activity- based protein profiling (ABPP) technology to radically expand the druggable content of the human proteome and develop high-quality chemical probes for genetically-defined protein targets in cancer and immuno- oncology. We have recently introduced advanced ABPP platforms that evaluate small-molecule interactions across thousands of proteins in parallel directly in native biological systems. By combining proteome-wide druggability maps of human cancer and immune cells furnished by ABPP with human genetic information, we have identified several high-priority cancer targets poised for chemical probe development. Optimized chemical probes will be used by our lab and a set of expert biology collaborators to characterize the functional relevance of protein targets in cancer and cancer-related immunology. We will also describe plans for continued technology innovation to further enhance chemical probe and target discovery by ABPP, including the following objectives – i) identify newly druggable E3 ligase systems capable of supporting targeted protein degradation in cancer cells; ii) discover chemical probes that selectively engage modified states of protein targets in cancer cells; and iii) generate advanced chemical libraries for ABPP to further increase the druggable fraction of the human cancer proteome. In summary, our research program should deliver high-quality chemical probes for, and pharmacological validation of, biologically compelling human cancer targets, providing critical knowledge to direct the future development of transformative cancer therapeutics. More generally, we envision that our research program will inspire chemical and cancer biologists to embrace the potential druggability of any human protein, as well as provide an experimental roadmap to realize this goal, for the benefit of both basic and translational research.

癌症研究和治疗大大受益于DNA测序方法的进步，这些方法的进步 加速了发现基因的发现，这些基因在突变后会促进肿瘤发生。的蛋白质产物 这些癌基因中的一些已成为开创性新药物的直接靶标。许多肿瘤基因， 但是，缺乏化学问题并且甚至不可能的蛋白质代码。在这些情况下， 我们对癌症分子基础的理解尚未转化为有效的新疗法。类似 可以在与癌症相关的免疫学（或免疫肿瘤学）中找到差异，其中人类遗传学正在发现 在先天和适应性免疫学中扮演基本角色的蛋白质；然而，这些蛋白质中的大多数都缺乏 化学问题。因此，癌症研究中出现了一个关键的挑战 - 如何获得大量收益 对现代人类遗传学遗赠的癌症和免疫学的理解被转化为新的 癌症的疗法？该研究计划的目的是利用和扩展我们实验室的创新活动 - 基于蛋白质分析（ABPP）技术，可以从根本上扩展人类蛋白质组的可药物含量 并为癌症和免疫 - 肿瘤学。我们最近推出了评估小分子互动的高级ABPP平台 直接在天然生物系统中并行跨越数千种蛋白质。通过结合全蛋白质组 ABPP提供的人类遗传信息提供的人类癌症和免疫细胞的可药性图，我们 已经确定了几种高优先癌靶标被中毒用于化学探针的发展。优化的化学物质 我们的实验室和一组专家生物学合作者将使用问题来表征功能相关性 蛋白质靶标的癌症和癌症相关免疫学。我们还将描述持续的计划 技术创新以进一步增强ABPP的化学探针和目标发现，包括以下 目标 - i）确定能够支持靶向蛋白质降解的新的可吸毒E3连接酶系统 在癌细胞中； ii）发现化学问题，可以选择性地接合癌症中蛋白质靶标的改良状态 细胞； iii）为ABPP生成高级化学文库，以进一步增加可吸毒的分数 人类癌症蛋白质组。总而言之，我们的研究计划应为 以及对生物学吸引人的人类癌症目标的药物验证，提供关键知识 指导变革性癌症治疗的未来发展。更普遍地，我们设想我们的 研究计划将激发化学和癌症生物学家接受任何可能的可药用 人类蛋白质，并提供实验路线图来实现这一目标，以使两种基本的利益 并翻译研究。