Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States.
Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.
J Med Chem. 2023 Jul 27;66(14):9445-9465. doi: 10.1021/acs.jmedchem.2c01859. Epub 2023 Jul 14.
Tissue transglutaminase (TG2) is a multifunctional enzyme involved in the cross-linking of extracellular matrix proteins, formation of complexes with fibronectin (FN) and integrins, and GTP hydrolysis. TG2 is activated in several pathological conditions, including cancer. We recently described a novel series of ligands that bind to TG2 and inhibit its interaction with FN. Because TG2 acts via multiple mechanisms, we set out to pursue a targeted protein degradation strategy to abolish TG2's myriad functions. Here, we report the synthesis and characterization of a series of VHL-based degraders that reduce TG2 in ovarian cancer cells in a proteasome-dependent manner. Degradation of TG2 resulted in significantly reduced cancer cell adhesion and migration in scratch-wound and migration assays. These results strongly indicate that further development of more potent and efficient TG2 degraders could be a new strategy for reducing the dissemination of ovarian and other cancers.
组织转谷氨酰胺酶（TG2）是一种多功能酶，参与细胞外基质蛋白的交联、与纤维连接蛋白（FN）和整合素形成复合物以及 GTP 水解。TG2 在多种病理条件下被激活，包括癌症。我们最近描述了一系列与 TG2 结合并抑制其与 FN 相互作用的新型配体。由于 TG2 通过多种机制发挥作用，我们着手追求一种靶向蛋白降解策略来消除 TG2 的多种功能。在这里，我们报告了一系列基于 VHL 的降解物的合成和表征，这些降解物以依赖蛋白酶体的方式减少卵巢癌细胞中的 TG2。TG2 的降解导致划痕和迁移实验中癌细胞黏附和迁移的显著减少。这些结果强烈表明，进一步开发更有效和高效的 TG2 降解物可能是减少卵巢癌和其他癌症扩散的一种新策略。
