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

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Discovery of a Highly Potent and Selective Degrader Targeting Hematopoietic Prostaglandin D Synthase via In Silico Design
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-15 , DOI: 10.1021/acs.jmedchem.1c01206
Hidetomo Yokoo ₁ , Norihito Shibata ₂ , Akinori Endo ₃ , Takahito Ito ₁ , Yuta Yanase _{1,

4} , Yuki Murakami _{1,

4} , Kiyonaga Fujii ₅ , Kengo Hamamura ₆ , Yasushi Saeki ₃ , Mikihiko Naito ₇ , Kosuke Aritake ₆ , Yosuke Demizu _{1,

4}

Affiliation

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.

中文翻译：

通过计算机设计发现针对造血前列腺素 D 合酶的高效选择性降解剂

通过蛋白水解靶向嵌合体（PROTAC）进行靶向蛋白质降解是药物发现和生物发现中令人兴奋的方式之一。开发过程中选择合适的接头、E3连接酶配体和靶蛋白配体非常重要；然而，需要通过反复试验来合成大量的PROTAC。在此，通过对造血前列腺素 D 合酶 (H-PGDS) 降解剂、H-PGDS 和 cereblon 的三元复合物进行对接模拟，我们成功开发了PROTAC(H-PGDS)-7 ( 6 )，该复合物显示出有效的选择性降解活性 (DC ₅₀ = 17.3 pM) 并有效抑制 KU812 细胞中前列腺素 D ₂的产生。此外，在使用心脏肥大的mdx小鼠的杜氏肌营养不良模型中，化合物6比强效 H-PGDS 抑制剂 TFC-007 表现出更好的炎症细胞因子抑制作用。因此，我们的结果表明，计算机模拟对于 PROTAC 的合理开发是有用的。

更新日期：2021-11-11

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