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，这些方法 加速了基因的发现，当基因发生突变时，会促进肿瘤的发生。中国的蛋白质产品 其中一些癌基因已经成为突破性新药的直接靶点。很多致癌基因， 然而，缺乏化学探针的蛋白质的代码甚至被认为是不可下药的。在这些情况下， 我们对癌症分子基础的了解尚未转化为有效的新疗法。一种类似的 可以在与癌症相关的免疫学(或免疫肿瘤学)中发现缺口，人类遗传学正在发现 在先天免疫和获得性免疫中起基础作用的蛋白质；然而，同样，这些蛋白质中的大多数缺乏 化学探头。因此，癌症研究中出现了一个关键挑战--如何才能在 现代人类遗传学对癌症和免疫学的理解将转化为新的 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- 基于蛋白质图谱(ABPP)技术从根本上扩大人类蛋白质组的可药物含量 并开发高质量的化学探针，用于癌症和免疫中基因定义的蛋白质靶标。 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并行地跨越数千种蛋白质。通过结合蛋白质组范围的 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易感性图谱，我们 已经确定了几个高优先级的癌症目标，准备开发化学探针。优化的化工产品 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 癌症和癌症相关免疫学中的蛋白质靶标。我们还将描述继续的计划 技术创新以进一步加强ABPP的化学探测和目标发现，包括以下内容 目标-i)确定能够支持靶向蛋白质降解的新的可药物E3连接酶系统 在癌细胞中；ii)发现选择性地与癌症中蛋白质靶标的修饰状态相结合的化学探针 细胞；以及iii)为ABPP建立先进的化学库，以进一步增加 人类癌症蛋白质组。总而言之，我们的研究计划应该为， 以及对生物学上令人信服的人类癌症靶点的药理学验证，提供关键知识 指导未来变革性癌症治疗的发展。更广泛地说，我们设想我们的 研究计划将激励化学和癌症生物学家接受任何潜在的可药性 人类蛋白质，以及为实现这一目标提供了一个实验路线图，为两者的基本利益 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.