MOLECULES
·
2022
·Vol. 27
·期 4
·1209
·
IF 4.927
Jiacheng He,Xianhua Lin,Fanhui Meng,Yumiao Zhao,Wei Wang,Yao Zhang,Xiaolei Chai,Ying Zhang,Weiwei Yu,Junjie Yang,Guichao Li,Xuekui Du,Hankun Zhang,Mingyao Liu,Weiqiang Lu
Metastatic pancreatic cancer remains a major clinical challenge, emphasizing the urgent need for the exploitation of novel therapeutic approaches with superior response. In this study, we demonstrate that the aberrant activation of prostaglandin E2(PGE2) receptor 4 (EP4) is a pro-metastatic signal in pancreatic cancer. To explore the therapeutic role of EP4 signaling, we developed a potent and selective EP4 antagonist L001 with single-nanomolar activity using a panel of cell functional assays. EP4 antagonism by L001 effectively repressed PGE2-elicited cell migration and the invasion of pancreatic cancer cells in a dose-dependent manner. Importantly, L001 alone or combined with the chemotherapy drug gemcitabine exhibited remarkably anti-metastasis activity in a pancreatic cancer hepatic metastasis model with excellent tolerability and safety. Mechanistically, EP4 blockade by L001 abrogated Yes-associated protein 1 (YAP)-driven pro-metastatic factor expression in pancreatic cancer cells. The suppression of YAP’s activity was also observed upon L001 treatment in vivo. Together, these findings support the notions that EP4–YAP signaling axis is a vital pro-metastatic pathway in pancreatic cancer and that EP4 inhibition with L001 may deliver a therapeutic benefit for patients with metastatic pancreatic cancer.Keywords:pancreatic cancer;metastasis;EP4;small molecule;YAP
研究领域:
肿瘤学
·
药理学
·
分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Zhiyuan Cheng,Yao Zhang,Limin Du,Wei Wang,Xiaolei Chai,Mengxian He,Hankun Zhang,Deyan Wu,Jian Lu,Sen Zhang,Bo Feng,Linlin Yang,Mingyao Liu,Weiqiang Lu
The development of dual prostaglandin E2 receptors 2/4 (EP2/EP4) antagonists represents an attractive strategy for cancer immunotherapy. Herein, a series of 4,7-dihydro-5H-thieno[2,3-c]pyran derivatives with potent EP2/EP4 dual antagonism were discovered by fine-tuned structural modifications. The biphenyl side chain was found to be the key pharmacophore for the transition from EP4 antagonism to EP2/EP4 dual antagonism. The introduction of large sterically hindered segments posed challenges on obtaining EP2 potency, while having minimal impact on EP4 potency. Molecular dynamics simulations verified that the EP2 pocket is relatively narrow compared to EP4, and the key residues surrounding the EP2 pocket impose spatial restrictions on the entry of antagonists. Representative compound 29 (CZY-1068) significantly reduced PGE2-induced expression of immunosuppression-related genes in macrophages. Notably, compound 29 elicited robust antitumor efficacy in the syngeneic MC38 tumor model. Taken together, this study provides a proof-of-concept for obtaining novel potent dual EP2/EP4 antagonists based on rational structural modifications.
研究领域:
药物化学
·
癌症研究
·
免疫学
·
药物研发
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Zhiyuan Cheng,Yijie Wang,Yao Zhang,Chan Zhang,Mengru Wang,Wei Wang,Jiacheng He,Yang Wang,Hankun Zhang,Qiansen Zhang,Chunyong Ding,Deyan Wu,Linlin Yang,Mingyao Liu,Weiqiang Lu
Nowadays, small-molecule drugs have become an indispensable part of tumor immunotherapy. Accumulating evidence has indicated that specifically blocking PGE2/EP4 signaling to induce robust antitumor immune response represents an attractive immunotherapy strategy. Herein, a 2H-indazole-3-carboxamide containing compound 1 was identified as a EP4 antagonist hit by screening our in-house small-molecule library. Systematic structure–activity relationship exploration leads to the discovery of compound 14, which displayed single-nanomolar EP4 antagonistic activity in a panel of cell functional assays, high subtype selectivity, and favorable drug-like profiles. Moreover, compound 14 profoundly inhibited the up-regulation of multiple immunosuppression-related genes in macrophages. Oral administration of compound 14, either as monotherapy or in combination with an anti-PD-1 antibody, significantly impaired tumor growth via enhancing cytotoxic CD8+ T cell-mediated antitumor immunity in a syngeneic colon cancer model. Thus, these results demonstrate the potential of compound 14 as a candidate for developing novel EP4 antagonists for tumor immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
药理学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2022
·
IF 8.039
Wei Wang,Jiacheng He,Junjie Yang,Chan Zhang,Zhiyuan Cheng,Yao Zhang,Qiansen Zhang,Peili Wang,Shuowen Tang,Xin Wang,Mingyao Liu,Weiqiang Lu,Han-Kun Zhang
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.
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2019
·
IF 6.054
Jun-Jie Yang,Wei-Wei Yu,Long-Long Hu,Wen-Juan Liu,Xian-Hua Lin,Wei Wang,Qiansen Zhang,Pei-Li Wang,Shuo-Wen Tang,Xin Wang,Mingyao Liu,Weiqiang Lu,Han-Kun Zhang
The prostanoid EP4 receptor is one of the key receptors associated with inflammatory mediator PGE2-elicited immunosuppression in the tumor microenvironment. Blockade of EP4 signaling to enhance immunity-mediated tumor elimination has recently emerged as a promising strategy for cancer immunotherapy. In our efforts to discover novel subtype-selective EP4 antagonists, we designed and synthesized a class of 1H-1,2,3-triazole-based ligands that display low nanomolar antagonism activity toward the human EP4 receptor and excellent subtype selectivity. The most promising compound 59 exhibits single-digit nanomolar potency in the EP4 calcium flux and cAMP-response element reporter assays and effectively suppresses the expression of multiple immunosuppression-related genes in macrophage cells. On the basis of its favorable ADMET properties, compound 59 was chosen for further in vivo biological evaluation. Oral administration of compound 59 significantly inhibited tumor growth in the mouse CT26 colon carcinoma model accompanied by enhanced infiltration of cytotoxic T lymphocytes in the tumor tissue.
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高影响因子
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