Mapping the Degradable Kinome: A Resource for Expedited Degrader Development

Targeted protein degradation refers to the use of small molecule inducers of ubiquitin-dependent degradation of proteins and enables the development of drugs to previously inaccessible targets. Degrader development is an empirical process due to a poor understanding of the key properties that require optimization. Here we established a synthetic chemistry and chemo-proteomics platform to annotate the ‘degradable kinome’. This first comprehensive dataset provides chemical leads for approximately 200 distinct kinase targets and demonstrates that the current practice of starting degrader design from the highest potency binder is often inadequate to generate an optimal degrader. This rich chemo-proteomic dataset supports the development of selective and multi-kinase degraders and also provides unique chemical tools to answer fundamental questions regarding ubiquitin-mediated kinase degradation, such as the requirement for p97 unfoldase activity for degradation by the proteasome. This work provides a blueprint for evaluating targeted degradation across entire gene families, which will serve to accelerate degrader development beyond the kinome.

靶向蛋白质降解（Targeted Protein Degradation）是指借助小分子诱导剂介导泛素依赖的蛋白质降解，为攻克此前难以成药的靶点开辟了全新的药物开发路径。由于对降解剂研发所需优化的关键性质缺乏深入认知，降解剂的开发目前仍属于经验驱动型流程。本研究构建了合成化学与化学蛋白质组学（chemo-proteomics）平台，用于注释“可降解激酶组”。本首份全面数据集为近200种不同的激酶靶点提供了化学先导化合物，并证实当前以最高活性结合物作为降解剂设计起点的常规策略，往往不足以获得最优降解剂。这份丰富的化学蛋白质组学数据集不仅为选择性及多激酶降解剂的开发提供了有力支撑，还提供了独特的化学工具，用于解答泛素介导的激酶降解相关的基础科学问题——例如蛋白酶体完成降解过程对p97解折叠酶活性的需求。本研究为全基因家族范围内的靶向降解评估提供了通用研发蓝图，有望推动激酶组之外的降解剂研发进程加速。