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Scaffold Hopping Strategy to Identify Prostanoid EP4 Receptor Antagonists for Cancer Immunotherapy
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-05-31 , DOI: 10.1021/acs.jmedchem.2c00448 Wei Wang 1 , Jiacheng He 1 , Junjie Yang 1 , Chan Zhang 1 , Zhiyuan Cheng 1 , Yao Zhang 1 , Qiansen Zhang 1 , Peili Wang 1 , Shuowen Tang 1 , Xin Wang 1 , Mingyao Liu 1 , Weiqiang Lu 1 , Han-Kun Zhang 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-05-31 , DOI: 10.1021/acs.jmedchem.2c00448 Wei Wang 1 , Jiacheng He 1 , Junjie Yang 1 , Chan Zhang 1 , Zhiyuan Cheng 1 , Yao Zhang 1 , Qiansen Zhang 1 , Peili Wang 1 , Shuowen Tang 1 , Xin Wang 1 , Mingyao Liu 1 , Weiqiang Lu 1 , Han-Kun Zhang 1
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Cancer cells can effectively suppress the natural immune response in humans, and prostaglandin E2 (PGE2) is a key mediator in the development of tumor cell resistance to immunotherapy. As a major contributor to PGE2-elicited immunosuppressive activity, the EP4 receptor promotes tumor development and progression in the tumor microenvironment, and the development of selective and potent EP4 receptor antagonists should have promising potential for tumor immunotherapy. Aiming at improving the drug-like properties, a series of 4,7-dihydro-5H-thieno[2,3-c]pyran derivatives were designed and synthesized through a scaffold hopping strategy. The most promising compound 47 exhibited good EP4 antagonistic activity and excellent subtype selectivity, as well as favorable drug-like properties. It effectively suppressed the expression of multiple immunosuppression-related genes in macrophages. Meanwhile, oral administration of compound 47, alone or in combination with anti-PD-1 antibody, significantly enhanced the antitumor immune response and inhibited tumor growth in the mouse CT26 colon carcinoma model.
中文翻译：
支架跳跃策略识别前列腺素 EP4 受体拮抗剂用于癌症免疫治疗
癌细胞可以有效抑制人体的自然免疫反应，而前列腺素E 2 (PGE 2 )是肿瘤细胞对免疫治疗产生耐药性的关键介质。作为 PGE 2引发的免疫抑制活性的主要贡献者，EP4 受体在肿瘤微环境中促进肿瘤的发展和进展，开发选择性和有效的 EP4 受体拮抗剂应该具有肿瘤免疫治疗的广阔潜力。为提高类药性能，通过支架跳跃策略设计合成了一系列4,7-二氢-5 H-噻吩并[2,3 - c ]吡喃衍生物。最有前途的化合物47表现出良好的EP4拮抗活性和优异的亚型选择性，以及良好的药物样特性。它有效地抑制了巨噬细胞中多种免疫抑制相关基因的表达。同时，在小鼠 CT26 结肠癌模型中，单独或与抗 PD-1 抗体联合口服化合物47可显着增强抗肿瘤免疫反应并抑制肿瘤生长。
更新日期：2022-05-31
中文翻译：
支架跳跃策略识别前列腺素 EP4 受体拮抗剂用于癌症免疫治疗
癌细胞可以有效抑制人体的自然免疫反应，而前列腺素E 2 (PGE 2 )是肿瘤细胞对免疫治疗产生耐药性的关键介质。作为 PGE 2引发的免疫抑制活性的主要贡献者，EP4 受体在肿瘤微环境中促进肿瘤的发展和进展，开发选择性和有效的 EP4 受体拮抗剂应该具有肿瘤免疫治疗的广阔潜力。为提高类药性能，通过支架跳跃策略设计合成了一系列4,7-二氢-5 H-噻吩并[2,3 - c ]吡喃衍生物。最有前途的化合物47表现出良好的EP4拮抗活性和优异的亚型选择性，以及良好的药物样特性。它有效地抑制了巨噬细胞中多种免疫抑制相关基因的表达。同时，在小鼠 CT26 结肠癌模型中，单独或与抗 PD-1 抗体联合口服化合物47可显着增强抗肿瘤免疫反应并抑制肿瘤生长。
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