Structure?activity relationship study of PROTACs against hematopoietic prostaglandin D<sub>2</sub> synthase
Structure?activity relationship study of PROTACs against hematopoietic prostaglandin D<sub>2</sub> synthase
复制标题
PROTACs抗造血前列腺素D<sub>2</sub>合酶构效关系研究
DOI：
10.1039/d2md00284a
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发表时间：
2022
影响因子：
4.1
通讯作者：
Demizu Yosuke
中科院分区：
文献类型：
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作者：
Murakami Yuki;Osawa Hinata;Kurohara Takashi;Yanase Yuta;Ito Takahito;Yokoo Hidetomo;Shibata Norihito;Naito Mikihiko;Aritake Kosuke;Demizu Yosuke
预期通过蛋白水解靶向嵌合体（PROTAC）降解造血前列腺素D2合酶（H-PGDS）在治疗过敏性疾病和杜氏肌营养不良症中是重要的。我们最近报道了由H-PGDS抑制剂（TFC-007）和cereblon（CRBN）E3连接酶配体（pomalidomide）组成的PROTAC（H-PGDS）-7（PROTAC 1）具有很强的H-PGDS降解活性。在此，我们研究了PROTAC 1的构效关系，重点是泊马度胺的C4-或C5-缀合，此外，H-PGDS配体从TFC-007与联芳醚交换为TAS-205与吡咯。评价了三种新的PROTAC的H-PGDS亲和力、H-PGDS降解活性和前列腺素D2产生的抑制。所有化合物均表现出较高的H-PGDS降解活性，但PROTAC（H-PGDS）-4-TAS-205（PROTAC 3）的活性略低于其他化合物。分子动力学模拟表明，PROTAC 3活性的降低可能是由于CRBN-PROTAC-H-PGDS三元复合物的稳定性较低。
Degradation of hematopoietic prostaglandin D2 synthase (H-PGDS) by proteolysis-targeting chimeras (PROTACs) is expected to be important in the treatment of allergic diseases and Duchenne's muscular dystrophy. We recently reported that PROTAC(H-PGDS)-7 (PROTAC1), which is composed of H-PGDS inhibitor (TFC-007) and cereblon (CRBN) E3 ligase ligand (pomalidomide), showed potent H-PGDS degradation activity. Here, we investigated the structure–activity relationships of PROTAC1, focusing on the C4- or C5-conjugation of pomalidomide, in addition, the H-PGDS ligand exchanging from TFC-007 with the biaryl ether to TAS-205 with the pyrrole. Three new PROTACs were evaluated for H-PGDS affinity, H-PGDS degrading activity, and inhibition of prostaglandin D2 production. All compounds showed high H-PGDS degrading activities, but PROTAC(H-PGDS)-4-TAS-205 (PROTAC3) was slightly less active than the other compounds. Molecular dynamics simulations suggested that the decrease in activity of PROTAC3 may be due to the lower stability of the CRBN-PROTAC-H-PGDS ternary complex.