Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Cell. 2020 Dec 10;183(6):1714-1731.e10. doi: 10.1016/j.cell.2020.10.038. Epub 2020 Dec 3.
Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. TPD is of interest in drug development, as it can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient process due to a lack of understanding of the relative importance of the key molecular events required to induce target degradation. Here, we use chemo-proteomics to annotate the degradable kinome. Our expansive dataset provides chemical leads for ∼200 kinases and demonstrates that the current practice of starting from the highest potency binder is an ineffective method for discovering active compounds. We develop multitargeted degraders to answer fundamental questions about the ubiquitin proteasome system, uncovering that kinase degradation is p97 dependent. This work will not only fuel kinase degrader discovery, but also provides a blueprint for evaluating targeted degradation across entire gene families to accelerate understanding of TPD beyond the kinome.
靶向蛋白降解（TPD）是指利用小分子诱导蛋白质的泛素依赖性降解。TPD 在药物开发中很有意义，因为它可以解决以前无法触及的靶点。然而，由于缺乏对诱导靶标降解所需的关键分子事件的相对重要性的理解，降解剂的发现和优化仍然是一个效率低下的过程。在这里，我们使用化学蛋白质组学来注释可降解的激酶组。我们广泛的数据集为约 200 个激酶提供了化学线索，并表明从最高效结合物开始的当前实践是发现活性化合物的无效方法。我们开发了多靶向降解剂来回答有关泛素蛋白酶体系统的基本问题，揭示了激酶降解依赖于 p97。这项工作不仅将推动激酶降解剂的发现，还为评估整个基因家族的靶向降解提供了蓝图，以加速对 TPD 的理解，超越激酶组。
