Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
ChemMedChem. 2024 Jan 15;19(2):e202300606. doi: 10.1002/cmdc.202300606. Epub 2023 Dec 6.
Prostaglandin E2 (PGE2) plays a key role in various stages of cancer. PGE2 signals through the EP2 and the EP4 receptors, promoting tumorigenesis, metastasis, and/or immune suppression. Dual inhibition of both the EP2 and the EP4 receptors has the potential to counteract the effect of PGE2 and to result in antitumor efficacy. We herein disclose for the first time the structure of dual EP2/EP4 antagonists. By merging the scaffolds of EP2 selective and EP4 selective inhibitors, we generated a new chemical series of compounds blocking both receptors with comparable potency. In vitro and in vivo profiling suggests that the newly identified compounds are promising lead structures for further development into dual EP2/EP4 antagonists for use in cancer therapy.
前列腺素 E2（PGE2）在癌症的各个阶段都发挥着关键作用。PGE2 通过 EP2 和 EP4 受体传递信号，促进肿瘤发生、转移和/或免疫抑制。双重抑制 EP2 和 EP4 受体有可能抵消 PGE2 的作用，并产生抗肿瘤疗效。我们首次披露了双重 EP2/EP4 拮抗剂的结构。通过合并 EP2 选择性和 EP4 选择性抑制剂的支架，我们生成了一个新的化合物系列，以相当的效力阻断这两个受体。体外和体内分析表明，新鉴定的化合物是进一步开发用于癌症治疗的双重 EP2/EP4 拮抗剂的有前途的先导结构。
