Discovery of 2H-Indazole-3-carboxamide Derivatives as Novel Potent Prostanoid EP4 Receptor Antagonists for Colorectal Cancer Immunotherapy

Abstract

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.

Spiro[3.3]heptane as a Saturated Benzene Bioisostere**

“…It is often used in medicinal chemistry as a 3D‐shaped scaffold [10,11] . However, to the best of our knowledge, it has never been used as a benzene bioisostere [12,13] …”

Design of Tracers in Fluorescence Polarization Assay for Extensive Application in Small Molecule Drug Discovery

“…As a kind of low molecular weight organic compound, the artificial small molecule is the key platform in medicine, molecular biology, and many other areas with its good biological activity and high selectivity. 96 In the past few years, the use of small molecules has developed into a promising drug discovery method, attracting more and more attention. With a molecular weight of less than approximately 900 Da, small molecules can quickly cross the cell membrane to reach the site where action is needed.…”

Discovery of a Highly Potent Oxysterol Receptor GPR183 Antagonist Bearing the Benzo[d]thiazole Structural Motif for the Treatment of Inflammatory Bowel Disease (IBD)

“…Therefore, we used the GloSensor cAMP assay to determine the antagonistic capacity of new compounds against GPR183. 28 As shown in Table 1, we first optimized the piperazine fragment of compound 4 to increase the structural novelty. Replacement of the piperazine moiety with bridged bicyclic piperazines or bicyclo [1.1.1] S2).…”