Discovery of ACT-1002-4271 as a Dual EP2/EP4 Antagonist with In Vivo Anti-Tumor Efficacy.

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2025-04-07 DOI:10.1002/cmdc.202500120

Olivier Corminboeuf, Isabelle Lyothier, Stefan Diethelm, Julien Pothier, Thierry Sifferlen, Davide Pozzi, Sylvia Richard-Bildstein, Hervé Siendt, Heinz Fretz, Christoph Boss, Lorenza Wyder, Sébastien Jeay, Ruben de Kanter, Carmela Gnerre, François Lehembre, Dominique S Meyer

引用次数: 0

Abstract

Prostaglandin E2 (PGE2) signalling via receptors EP2 and EP4 is involved in various aspects of cancer and has been shown to promote tumor progression, metastasis, and immune evasion. Inhibition of PGE2 signaling by blockade of the EP2 and EP4 receptors has the potential to counteract the tumor-promoting effects of PGE2. We herein present the discovery of compound 30 (ACT-1002-4271), a dual EP2/EP4 antagonist with single digit nanomolar potency on both receptors. Our medicinal chemistry strategy is based on fine-tuning of the substitution pattern on an EP2 selective starting point to achieve dual EP2/EP4 antagonism. ACT-1002-4271 demonstrated significant anti-tumor efficacy in an EMT-6 mouse model when administered subcutaneously.

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ACT-1002-4271作为EP2/EP4双重拮抗剂的体内抗肿瘤疗效的发现

前列腺素 E2（PGE2）通过 EP2 和 EP4 受体发出的信号参与了癌症的各个方面，并被证明能促进肿瘤的发展、转移和免疫逃避。通过阻断 EP2 和 EP4 受体来抑制 PGE2 信号传导有可能抵消 PGE2 的肿瘤促进作用。我们在此介绍发现的化合物 30 (ACT-1002-4271)，它是一种 EP2/EP4 双拮抗剂，对两种受体的效力均为个位数纳摩尔。我们的药物化学策略基于对 EP2 选择性起点的取代模式进行微调，以实现 EP2/EP4 双拮抗。皮下注射 ACT-1002-4271 在 EMT-6 小鼠模型中显示出显著的抗肿瘤疗效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

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