Nalawansha Dhanusha A, Li Ke, Hines John, Crews Craig M
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, United States.
Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States.
J Am Chem Soc. 2022 Mar 30;144(12):5594-5605. doi: 10.1021/jacs.2c00874. Epub 2022 Mar 21.
Targeted protein degradation (TPD) by PROTACs is a promising strategy to control disease-causing protein levels within the cell. While TPD is emerging as an innovative drug discovery paradigm, there are currently only a limited number of E3 ligase:ligand pairs that are employed to induce protein degradation. Herein, we report a novel approach to induce protein degradation by hijacking a methyl reader:E3 ligase complex. L3MBTL3 is a methyl-lysine reader protein that binds to the Cul4 E3 ligase complex and targets methylated proteins for proteasomal degradation. By co-opting this natural mechanism, we report the design and biological evaluation of L3MBTL3-recruiting PROTACs and demonstrate nuclear-specific degradation of FKBP12 and BRD2. We envision this as a generalizable approach to utilize other reader protein-associated E3 ligase complexes in PROTAC design to expand the E3 ligase toolbox and explore the full potential of TPD.
通过PROTAC进行靶向蛋白质降解（TPD）是一种控制细胞内致病蛋白水平的有前景的策略。虽然TPD正在成为一种创新的药物发现范式，但目前用于诱导蛋白质降解的E3连接酶：配体对数量有限。在此，我们报告了一种通过劫持甲基阅读器：E3连接酶复合物来诱导蛋白质降解的新方法。L3MBTL3是一种甲基赖氨酸阅读器蛋白，它与Cul4 E3连接酶复合物结合，并将甲基化蛋白靶向蛋白酶体降解。通过利用这种天然机制，我们报告了招募L3MBTL3的PROTAC的设计和生物学评估，并证明了FKBP12和BRD2的核特异性降解。我们设想这是一种通用方法，可在PROTAC设计中利用其他与阅读器蛋白相关的E3连接酶复合物来扩展E3连接酶工具箱并探索TPD的全部潜力。
