Chemical Proteomic Platforms for Radically Expanding Cancer Druggability

癌症研究和治疗极大地受益于DNA测序方法的进步， 加速了基因的发现，当突变时，会促进肿瘤的发生。的蛋白质产物 这些致癌基因中的一些已经成为突破性新药的直接靶点。许多致癌基因， 然而，编码蛋白质缺乏化学探针，甚至被认为是不可药用的。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。类似的 在癌症相关的免疫学（或免疫肿瘤学）中可以找到差距，人类遗传学正在发现 在先天免疫和适应性免疫中发挥重要作用的蛋白质;然而，这些蛋白质中的大多数又缺乏 化学探针因此，癌症研究中出现了一个关键的挑战--如何才能在癌症研究中取得巨大的进展？ 现代人类遗传学对癌症和免疫学的理解将被转化为新的 癌症的治疗方法？这项研究计划的目标是利用和扩展我们实验室的创新活动- 基于蛋白质谱分析（ABPP）技术，从根本上扩大了人类蛋白质组的可药用内容 并开发用于癌症和免疫中遗传定义的蛋白质靶点的高质量化学探针 肿瘤学我们最近推出了先进的ABPP平台，用于评估小分子相互作用 直接在天然生物系统中平行地跨越数千种蛋白质。通过结合蛋白质组 由ABPP提供的具有人类遗传信息的人类癌症和免疫细胞的药物敏感性图谱，我们 已经确定了几个高度优先的癌症目标，为化学探针的发展做好了准备。优化化学品 我们的实验室和一组专业生物学合作者将使用探针来表征功能相关性 癌症和癌症相关免疫学中的蛋白质靶点。我们还将描述计划继续 技术创新，以进一步提高ABPP的化学探针和目标发现，包括以下内容 目的- i）鉴定能够支持靶蛋白降解的新的可药物化E3连接酶系统 ii）发现化学探针，其选择性地接合癌症中蛋白质靶标的修饰状态 iii）产生ABPP的先进化学文库，以进一步增加细胞的可药用部分， 人类癌症蛋白质组。总之，我们的研究计划应该提供高质量的化学探针， 和药理学验证，生物学上引人注目的人类癌症靶点，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， 一项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可药用性。 人类蛋白质，以及提供一个实验路线图，以实现这一目标，为双方的基本利益 和翻译研究。

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.