Discovery and Characterization of 1<i>H</i>-1,2,3-Triazole Derivatives as Novel Prostanoid EP4 Receptor Antagonists for Cancer Immunotherapy

Yang, Junjie; Yu, Weiwei; Hu, Longlong; Liu, Wenjuan; Lin, Xian-Hua; Wang, Wei; Zhang, Qiansen; Wang, Peili; Tang, Shuowen; Wang, Xin; Liu, Mingyao; Lü, Weiqiang; Zhang, Han-Kun

doi:10.1021/acs.jmedchem.9b01269

Cited by 33 publications

(19 citation statements)

References 57 publications

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“…To identify a potent small molecule EP4 antagonist with therapeutic potential in OA, we screened a class of small molecule compounds with 1H-1,2,3-triazole-based structures 57 , with osteoclast differentiation as the primary outcome. HL-43, which refers to compound 43 in the library, was the most potent inhibitor of PGE2-induced osteoclast differentiation (Fig.…”

Section: Resultsmentioning

confidence: 99%

PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis

et al. 2022

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Prostaglandin E2 (PGE2), a major cyclooxygenase-2 (COX-2) product, is highly secreted by the osteoblast lineage in the subchondral bone tissue of osteoarthritis (OA) patients. However, NSAIDs, including COX-2 inhibitors, have severe side effects during OA treatment. Therefore, the identification of novel drug targets of PGE2 signaling in OA progression is urgently needed. Osteoclasts play a critical role in subchondral bone homeostasis and OA-related pain. However, the mechanisms by which PGE2 regulates osteoclast function and subsequently subchondral bone homeostasis are largely unknown. Here, we show that PGE2 acts via EP4 receptors on osteoclasts during the progression of OA and OA-related pain. Our data show that while PGE2 mediates migration and osteoclastogenesis via its EP2 and EP4 receptors, tissue-specific knockout of only the EP4 receptor in osteoclasts (EP4LysM) reduced disease progression and osteophyte formation in a murine model of OA. Furthermore, OA-related pain was alleviated in the EP4LysM mice, with reduced Netrin-1 secretion and CGRP-positive sensory innervation of the subchondral bone. The expression of platelet-derived growth factor-BB (PDGF-BB) was also lower in the EP4LysM mice, which resulted in reduced type H blood vessel formation in subchondral bone. Importantly, we identified a novel potent EP4 antagonist, HL-43, which showed in vitro and in vivo effects consistent with those observed in the EP4LysM mice. Finally, we showed that the Gαs/PI3K/AKT/MAPK signaling pathway is downstream of EP4 activation via PGE2 in osteoclasts. Together, our data demonstrate that PGE2/EP4 signaling in osteoclasts mediates angiogenesis and sensory neuron innervation in subchondral bone, promoting OA progression and pain, and that inhibition of EP4 with HL-43 has therapeutic potential in OA.

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Section: Resultsmentioning

confidence: 99%

PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis

et al. 2022

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“…Our and other groups have reported a panel of EP4 antagonists in the past years [30,[45][46][47]. Small molecule L001 represents a next-generation EP4 antagonist harboring a functional carboxamido-benzoic acid skeleton.…”

Section: Discussionmentioning

confidence: 98%

A Novel Small Molecular Prostaglandin Receptor EP4 Antagonist, L001, Suppresses Pancreatic Cancer Metastasis

Lin

Meng

et al. 2022

Molecules

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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.

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“…For example, cyclic enone ( 23 ) with vinyl azide ( 24 ; α-azidostyrene) catalyzed by DBU furnished the corresponding C / N -divinyl-1,2,3-triazole ( 25 ) ( Supplementary Figure S3B ). These C -vinyl- and N -vinyl-triazoles have many biological activities, including EP4 receptor antagonists, α-glycosidase inhibition, antitubercular, antimicrobial, tubulin inhibition, and anti-inflammatory properties ( Yang et al, 2020 ).…”

Section: Synthetic Approachesmentioning

confidence: 99%

Triazoles and Their Derivatives: Chemistry, Synthesis, and Therapeutic Applications

Matin

Chakraborty

Rahman

et al. 2022

Front. Mol. Biosci.

146

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Among the nitrogen-containing heterocyclic compounds, triazoles emerge with superior pharmacological applications. Structurally, there are two types of five-membered triazoles: 1,2,3-triazole and 1,2,4-triazole. Due to the structural characteristics, both 1,2,3- and 1,2,4-triazoles are able to accommodate a broad range of substituents (electrophiles and nucleophiles) around the core structures and pave the way for the construction of diverse novel bioactive molecules. Both the triazoles and their derivatives have significant biological properties including antimicrobial, antiviral, antitubercular, anticancer, anticonvulsant, analgesic, antioxidant, anti-inflammatory, and antidepressant activities. These are also important in organocatalysis, agrochemicals, and materials science. Thus, they have a broad range of therapeutic applications with ever-widening future scope across scientific disciplines. However, adverse events such as hepatotoxicity and hormonal problems lead to a careful revision of the azole family to obtain higher efficacy with minimum side effects. This review focuses on the structural features, synthesis, and notable therapeutic applications of triazoles and related compounds.

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Discovery and Characterization of 1H-1,2,3-Triazole Derivatives as Novel Prostanoid EP4 Receptor Antagonists for Cancer Immunotherapy

Cited by 33 publications

References 57 publications

PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis

PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis

A Novel Small Molecular Prostaglandin Receptor EP4 Antagonist, L001, Suppresses Pancreatic Cancer Metastasis

Triazoles and Their Derivatives: Chemistry, Synthesis, and Therapeutic Applications

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