Department of Chemistry, University of California, Berkeley, CA, 94720, USA.
Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.
Sci Rep. 2020 Sep 23;10(1):15543. doi: 10.1038/s41598-020-72491-9.
Targeted protein degradation (TPD) has emerged as a powerful tool in drug discovery for the perturbation of protein levels using heterobifunctional small molecules. E3 ligase recruiters remain central to this process yet relatively few have been identified relative to the ~ 600 predicted human E3 ligases. While, initial recruiters have utilized non-covalent chemistry for protein binding, very recently covalent engagement to novel E3's has proven fruitful in TPD application. Herein we demonstrate efficient proteasome-mediated degradation of BRD4 by a bifunctional small molecule linking the KEAP1-Nrf2 activator bardoxolone to a BRD4 inhibitor JQ1.
靶向蛋白降解（TPD）已成为药物发现领域的一种强大工具，可使用杂双功能小分子来干扰蛋白质水平。E3 连接酶招募物在这个过程中仍然是核心，但相对于约 600 种预测的人类 E3 连接酶，相对较少被鉴定出来。虽然最初的招募物利用非共价化学结合蛋白，但最近共价结合到新型 E3 连接酶在 TPD 应用中被证明是富有成效的。在此，我们通过将 KEAP1-Nrf2 激活剂 bardoxolone 与 BRD4 抑制剂 JQ1 连接的双功能小分子，证明了 BRD4 的蛋白酶体介导的有效降解。
