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.

癌症研究和治疗极大地受益于 DNA 测序方法的进步， 加速了基因突变后促进肿瘤发生的蛋白质产物的发现。 其中一些致癌基因已成为许多突破性新药的直接靶标， 然而，编码缺乏化学探针的蛋白质，甚至被认为是不可成药的。 我们对癌症分子基础的理解尚未转化为有效的新疗法。 差距可以在与癌症相关的免疫学（或免疫肿瘤学）中找到，人类遗传学正在发现这一点 在先天性和适应性免疫中发挥重要作用的蛋白质；然而，大多数这些蛋白质又缺乏 因此，癌症研究中出现了一个关键挑战——如何才能取得巨大成果。 现代人类遗传学遗留下来的对癌症和免疫学的理解被转化为新的 该研究项目的目标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，从根本上扩展人类蛋白质组的可药物含量 并为癌症和免疫中基因定义的蛋白质靶点开发高质量的化学探针 我们最近推出了评估小分子相互作用的先进 ABPP 平台。 通过结合整个蛋白质组，直接在天然生物系统中并行处理数千个蛋白质。 ABPP 提供的人类癌症和免疫细胞的成药性图谱以及人类遗传信息，我们 已经确定了几个准备用于化学探针开发的高优先级癌症靶点。 我们的实验室和一组专家生物学合作者将使用探针来表征功能相关性 我们还将描述癌症和癌症相关免疫学中的蛋白质靶标的持续计划。 技术创新进一步增强 ABPP 的化学探测和靶标发现，包括以下内容 目标 – i) 确定能够支持靶向蛋白质降解的新型可成药 E3 连接酶系统 在癌细胞中；ii) 发现选择性地参与癌症中蛋白质靶标的修饰状态的化学探针 细胞；以及 iii) 为 ABPP 生成先进的化学库，以进一步增加药物的可成药部分 总之，我们的研究计划应该提供高质量的化学探针， 对具有生物学意义的人类癌症靶点进行药理学验证，提供关键知识 指导变革性癌症疗法的未来发展 更一般地说，我们设想我们的方法。 研究计划将激励化学和癌症生物学家接受任何药物的潜在成药性 人类蛋白质，并提供实现这一目标的实验路线图，以造福于基本 和转化研究。