Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 2, Pages 569-590Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01269
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Funding
- National Key RAMP
- D Program of China [2018YFA0507001]
- Shanghai Committee of Science and Technology [18431900100, 18431900500, 19ZR1473500]
- Innovation Program of Shanghai Municipal Education Commission [2017-01-07-00-05-E00011]
- National Natural Science Foundation of China [21977032, 81830083, 81972828]
- Shenzhen Municipal Government of China [KQTD2017081060226082]
- ECNU Multifunctional Platform for Innovation [011]
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The prostanoid EP4 receptor is one of the key receptors associated with inflammatory mediator PGE(2)-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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