Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Cell Chem Biol. 2018 Jan 18;25(1):88-99.e6. doi: 10.1016/j.chembiol.2017.10.005. Epub 2017 Nov 9.
Heterobifunctional molecules that recruit E3 ubiquitin ligases, such as cereblon, for targeted protein degradation represent an emerging pharmacological strategy. A major unanswered question is how generally applicable this strategy is to all protein targets. In this study, we designed a multi-kinase degrader by conjugating a highly promiscuous kinase inhibitor with a cereblon-binding ligand, and used quantitative proteomics to discover 28 kinases, including BTK, PTK2, PTK2B, FLT3, AURKA, AURKB, TEC, ULK1, ITK, and nine members of the CDK family, as degradable. This set of kinases is only a fraction of the intracellular targets bound by the degrader, demonstrating that successful degradation requires more than target engagement. The results guided us to develop selective degraders for FLT3 and BTK, with potentials to improve disease treatment. Together, this study demonstrates an efficient approach to triage a gene family of interest to identify readily degradable targets for further studies and pre-clinical developments.
招募 E3 泛素连接酶（如 cereblon）进行靶向蛋白降解的杂双功能分子代表了一种新兴的药理学策略。一个尚未解决的主要问题是，这种策略在多大程度上适用于所有蛋白质靶标。在这项研究中，我们通过将一种高混杂的激酶抑制剂与 cereblon 结合配体连接，设计了一种多激酶降解剂，并使用定量蛋白质组学发现了 28 种激酶，包括 BTK、PTK2、PTK2B、FLT3、AURKA、AURKB、TEC、ULK1、ITK 和 CDK 家族的九个成员，这些激酶均可被降解。这组激酶只是该降解剂结合的细胞内靶标的一小部分，表明成功的降解需要的不仅仅是靶标结合。这些结果指导我们开发了针对 FLT3 和 BTK 的选择性降解剂，有可能改善疾病的治疗效果。总之，这项研究展示了一种有效的方法，可以对感兴趣的基因家族进行分类，以确定可进一步研究和临床前开发的易于降解的靶标。
