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.
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.
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