Discovery of a Highly Potent and Selective Degrader Targeting Hematopoietic Prostaglandin D Synthase via In Silico Design

Targeted
protein degradation by proteolysis-targeting chimera (PROTAC)
is one of the exciting modalities for drug discovery and biological
discovery. It is important to select an appropriate linker, an E3
ligase ligand, and a target protein ligand in the development; however,
it is necessary to synthesize a large number of PROTACs through trial
and error. Herein, using a docking simulation of the ternary complex
of a hematopoietic prostaglandin D synthase (H-PGDS) degrader, H-PGDS,
and cereblon, we have succeeded in developing PROTAC­(H-PGDS)-7 (6), which showed potent and selective degradation
activity (DC50 = 17.3 pM) and potent suppression of prostaglandin
D2 production in KU812 cells. Additionally, in a Duchenne
muscular dystrophy model using mdx mice with cardiac
hypertrophy, compound 6 showed better inhibition of inflammatory
cytokines than a potent H-PGDS inhibitor TFC-007. Thus, our results
demonstrated that in silico simulation would be useful for the rational
development of PROTACs.

蛋白水解靶向嵌合体（proteolysis-targeting chimera, PROTAC）介导的靶向蛋白降解，是药物研发与生命科学研究领域极具前景的技术策略之一。在PROTAC的开发过程中，合理选择连接子（linker）、E3泛素连接酶配体与靶蛋白配体至关重要，但传统研发模式往往需要通过大量试错来合成PROTAC分子。本研究通过对造血型前列腺素D合酶（hematopoietic prostaglandin D synthase, H-PGDS）降解剂、H-PGDS与脑蛋白（cereblon）所形成的三元复合物开展分子对接模拟，成功开发出PROTAC(H-PGDS)-7（编号6），该化合物在KU812细胞中展现出强效且高选择性的蛋白降解活性（DC50=17.3皮摩尔），并可有效抑制前列腺素D2的生成。此外，在携带心肌肥厚的杜氏肌营养不良症（Duchenne muscular dystrophy, DMD）mdx小鼠模型中，化合物6对炎症细胞因子的抑制效果优于强效H-PGDS抑制剂TFC-007。综上，本研究结果证实，虚拟模拟（in silico simulation）辅助策略可用于PROTAC的理性研发。