Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-9501, Japan.
Division of Biochemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-9501, Japan.
J Med Chem. 2021 Nov 11;64(21):15868-15882. doi: 10.1021/acs.jmedchem.1c01206. Epub 2021 Oct 15.
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 (), which showed potent and selective degradation activity (DC = 17.3 pM) and potent suppression of prostaglandin D production in KU812 cells. Additionally, in a Duchenne muscular dystrophy model using mice with cardiac hypertrophy, compound 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（PROTAC）介导的靶向蛋白降解是药物发现和生物发现令人兴奋的模式之一。在开发过程中，选择合适的连接子、E3 连接酶配体和靶蛋白配体非常重要；然而，有必要通过反复试验来合成大量的 PROTAC。在此，我们通过对造血前列腺素 D 合酶（H-PGDS）降解物、H-PGDS 和 cereblon 的三元复合物的对接模拟，成功开发了（），其表现出强大且选择性的降解活性（DC = 17.3 pM），并能有效抑制 KU812 细胞中前列腺素 D 的产生。此外，在使用具有心脏肥大的 小鼠的杜氏肌营养不良症模型中，化合物 显示出比强效 H-PGDS 抑制剂 TFC-007 更好的抑制炎性细胞因子的作用。因此，我们的结果表明，计算模拟将有助于合理开发 PROTAC。
