- |||||||||| treprostinil / Generic mfg.
Treprostinil Inhibits Human Lung Fibroblast Matrix Production Via the IP Receptor Independently of cAMP (San Diego Convention Center, Area E (Hall A-B2, Ground Level)) - Feb 20, 2024 - Abstract #ATS2024ATS_2035;
Recent clinical trials show that inhaled Treprostinil (Tre), a stable analogue of prostacyclin, mitigated the decline of pulmonary function in patients with IPF. These findings suggest the antifibrotic effects of Treprostinil are mediated through the IP receptor in a cAMP independent manner since both Isoproterenol and PGE2 induce more cAMPi but have less effect on extracellular matrix production as measure by COL1A1 and PAI-1.
- |||||||||| Journal: Design of Dual EP2/EP4 Antagonists through Scaffold Merging of Selective Inhibitors. (Pubmed Central) - Jan 18, 2024
By merging the scaffolds of EP2 selective and EP4 selective inhibitors, we generated a new chemical series of compounds blocking both receptors with comparable potency. In vitro and in vivo profiling suggests that the newly identified compounds are promising lead structures for further development into dual EP2/EP4 antagonists for use in cancer therapy.
- |||||||||| ASP7657 / Astellas
Preclinical, Journal: Blockade of EP4 by ASP7657 Modulates Myeloid Cell Differentiation In Vivo and Enhances the Antitumor Effect of Radiotherapy. (Pubmed Central) - Dec 11, 2023
Notably, ASP7657 also significantly enhanced the antitumor efficacy of radiotherapy in an anti-PD-1 antibody refractory model. These results indicate that the therapeutic potential of ASP7657 arises via upregulation of DCs and subsequent CD8 T cell activation in addition to suppression of MDSCs in mouse models and that combining EP4 antagonists with radiotherapy or an anti-PD-1 antibody can improve antitumor efficacy.
- |||||||||| Journal: Docking for EP4R antagonists active against inflammatory pain. (Pubmed Central) - Dec 11, 2023
Further, we show how structure-based optimization of initial docking hits identifies a potent and selective antagonist with 16 nanomolar potency. Finally, we demonstrate favorable pharmacokinetics for the discovered compound as well as anti-allodynic and anti-inflammatory activity in several preclinical pain models in mice.
- |||||||||| Biomarker, Review, Journal, IO biomarker: Small molecule inhibitors for cancer immunotherapy and associated biomarkers - the current status. (Pubmed Central) - Dec 3, 2023
In addition, immunosuppressive signals via adenosine can be counteracted by CD39 and CD73 inhibition, while suppression via intratumoral immunosuppressive prostaglandin E can be targeted by EP2/EP4 antagonists. Here, we present the status of the most promising small molecule drug candidates for cancer immunotherapy, all residing relatively early in development, and the potential of relevant biomarkers.
- |||||||||| Journal: The severity of NEC is ameliorated by prostaglandin E2 through regulating intestinal microcirculation. (Pubmed Central) - Aug 21, 2023
This response to PGE2 was involved in eNOS phosphorylation and nitric oxide (NO) production and was blocked by the EP4 antagonist in vitro, suggesting that targeting the PGE2-EP4-eNOS axis might be a potential clinical and therapeutic strategy for NEC treatment. The study is reported in accordance with ARRIVE guidelines ( https://arriveguidelines.org ).
- |||||||||| palupiprant (AN0025) / Eisai, Adlai Nortye
Preclinical, Journal: Discovery of Novel, Selective Prostaglandin EP4 Receptor Antagonists with Efficacy in Cancer Models. (Pubmed Central) - Jun 15, 2023
Due to favorable pharmacokinetics properties and good oral bioavailability (F = 76%), compound 36 was chosen for in vivo efficacy studies. Compound 36 inhibited tumor growth in a CT-26 colon cancer xenograft better than E7046 and a combination of 36 with capecitabine significantly suppressed tumor growth (TGI up to 94.26%) in mouse models.
- |||||||||| Keytruda (pembrolizumab) / Merck (MSD), TPST-1495 / Tempest Therap
A phase 1 study of TPST-1495 as a single agent and in combination with pembrolizumab in patients with advanced solid tumors. (On Demand | Hall A; Poster Bd # 305) - Apr 26, 2023 - Abstract #ASCO2023ASCO_1808;
P1a/1b
TPST-1495 is a novel oral therapy that inhibits signaling only at the tumor promoting EP2/EP4 receptors. In patients with heavily treated solid tumors, primarily MSS CRC, TPST-1495 had pharmacodynamic activity, a manageable safety profile, and a potential signal of activity consistent with the preclinical data and IO combination mechanism.
- |||||||||| KF-0210 / Keythera Pharma
Discovery of EP4 receptor antagonist KF-0210 for the treatment of cancers (Section 45; Poster Board #11) - Mar 14, 2023 - Abstract #AACR2023AACR_3609;
It shows the inhibitory effect on tumor growth in mouse models of colorectal and breast cancers. The combination treatment of KF-0210 and PD-1/PD-L1 antibodies shows a superior therapeutic effect compared to the monotherapy of each treatment.
- |||||||||| Journal, Immunomodulating: Tailored PGE2 Immunomodulation of moDCs by Nano-Encapsulated EP2/EP4 Antagonists. (Pubmed Central) - Jan 22, 2023
Even though both antagonists showed a burst release within 15 min at 37 °C, the nanoparticles executed the immunomodulatory effects on moDCs. In summary, we demonstrate the functionality of EP2/EP4 antagonist-loaded nanoparticles to overcome PGE2 modulation of moDCs.
- |||||||||| indomethacin / Generic mfg.
Disruption of PGE Receptor EP4 Signaling Resulting in Mouse Patent Ductus Arteriosus (PDA) is Dependent on Developmental Timing. (P1&2, Plaza Level) - Jan 22, 2023 - Abstract #SRI2023SRI_342;
While other studies note that EP4 KO DAs have impaired fibromuscular remodeling and secondary closure, our data suggest that delayed developmental maturity is the underlying cause. These findings coincide with observations of PDA in the offspring of mothers treated with indomethacin tocolysis later in gestation and suggest that exposure to PGE2 is critical for intact development of DA maturation and sensing mechanisms at birth.
- |||||||||| Opdivo (nivolumab) / Ono Pharma, BMS, BMS-986310 / BMS, Ono Pharma
P1 data, Journal: First-in-human study of ONO-4578, an antagonist of prostaglandin E receptor 4, alone and with nivolumab in solid tumors. (Pubmed Central) - Sep 13, 2022
P1
Considering safety, efficacy, and pharmacokinetics/pharmacodynamics results, ONO-4578 40 mg daily with nivolumab 240 mg biweekly was selected as the recommended dose for future clinical trials. (Registration: JapicCTI-173496 and NCT03155061).
- |||||||||| Biomarker, Journal, Tumor microenvironment, IO biomarker: PGE-EP2/EP4 signaling elicits immunosuppression by driving the mregDC-Treg axis in inflammatory tumor microenvironment. (Pubmed Central) - Jun 15, 2022
Importantly, the EP2/EP4 expression level is strongly correlated with the gene signatures of both active inflammation and the mregDC-Treg axis and has significant prognosis value in various human cancers. Thus, PGE-EP2/EP4 signaling functions as the key regulatory node linking active inflammation and immunosuppression in TME, which can be targeted by EP2 and EP4 antagonists for cancer therapeutics.
- |||||||||| Journal, PD(L)-1 Biomarker, IO biomarker: Scaffold Hopping Strategy to Identify Prostanoid EP4 Receptor Antagonists for Cancer Immunotherapy. (Pubmed Central) - Jun 11, 2022
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.
- |||||||||| Tailored PGE2 immunomodulation of moDCs by next-generation nano-encapsulated EP2/EP4 antagonists () - May 9, 2022 - Abstract #CIMT2022CIMT_99;
Yet, the combined encapsulation of both antagonists in the same nanoparticle showed a significantly lower co-stimulatory marker expression compared to separately encapsulated antagonists. In summary, we demonstrate the functionality of the EP2 and EP4 antagonists PLGA nanoparticles to overcome PGE2 modulation of moDCs in vitro.
- |||||||||| Journal, PD(L)-1 Biomarker, IO biomarker: The COX-2-PGE2 pathway promotes tumor evasion in colorectal adenomas. (Pubmed Central) - May 6, 2022
They may provide the rationale for developing new therapeutic approaches to subvert this process by targeting immune checkpoint pathways using EP4 antagonists. In addition, our findings reveal a novel mechanism explaining how NSAIDs reduce colorectal cancer risk by suppressing tumor immune evasion.
- |||||||||| indomethacin / Generic mfg.
Journal, IO biomarker: Endosomal TLR3 signaling in stromal osteoblasts induces prostaglandin E-mediated inflammatory periodontal bone resorption. (Pubmed Central) - Apr 19, 2022
In addition, we found that indomethacin (a COX-2 inhibitor) or an antagonist of the PGE receptor EP4 attenuated the poly(I:C)-induced PGE production and subsequent Tnfsf11 expression...These data suggest that TLR3 signaling in osteoblasts controls PGE production and induces the subsequent differentiation and survival of mature osteoclasts. Endogenous TLR3 in stromal osteoblasts and osteoclasts synergistically induces inflammatory alveolar bone resorption in periodontitis.
- |||||||||| Kisqali (ribociclib) / Novartis
Journal: Proliferation of bovine endometrial epithelial cells is promoted by prostaglandin E-PTGER2 signaling through cell cycle regulation. (Pubmed Central) - Mar 23, 2022
These processes were down-regulated by PTGER2 antagonist AH6809 and CDK inhibitors (LEE011, CDK2 Inhibitor II and Ro 3306)...Our data demonstrate that PGE-PTGER2 signaling activation has a direct molecular association with cell cycle regulation and cell proliferation in bEECs. Collectively, these findings will improve our understanding of the roles for PGE-PTGER2 signaling activation in the physiological and pharmacological processes of bovine endometrium.
- |||||||||| Journal, PD(L)-1 Biomarker, IO biomarker: Single-cell analysis reveals EP4 as a target for restoring T cell infiltration and sensitizing prostate cancer to immunotherapy. (Pubmed Central) - Mar 23, 2022
Collectively, these findings will improve our understanding of the roles for PGE-PTGER2 signaling activation in the physiological and pharmacological processes of bovine endometrium. Our study identified EP4 as a specific target for prostate cancer immunotherapy and demonstrated that YY001 inhibited the growth of prostate tumors by regulating the immune microenvironment and strongly synergized with anti-PD-1 antibodies to convert completely unresponsive prostate cancers into responsive cancers, resulting in marked tumor regression, long-term survival, and lasting immunologic memory.
- |||||||||| Journal: PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis. (Pubmed Central) - Mar 11, 2022
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.
- |||||||||| gemcitabine / Generic mfg.
Journal: A Novel Small Molecular Prostaglandin Receptor EP4 Antagonist, L001, Suppresses Pancreatic Cancer Metastasis. (Pubmed Central) - Mar 5, 2022
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...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.
- |||||||||| desmopressin / Generic mfg.
Journal: A Vasopressin-Induced Change in Prostaglandin Receptor Subtype Expression Explains the Differential Effect of PGE on AQP2 Expression. (Pubmed Central) - Feb 8, 2022
Our study shows that in mpkCCD cells, reduced EP4 receptor and increased EP1/FP receptor expression by dDAVP explains the differential effects of PGE and PGF on AQP2 abundance with or without dDAVP. As the V2R and EP4 receptor, but not the EP1 and FP receptor, can couple to Gs and stimulate the cyclic adenosine monophosphate (cAMP) pathway, our data support a view that cells can desensitize themselves for receptors activating the same pathway and sensitize themselves for receptors of alternative pathways.
- |||||||||| Erbitux (cetuximab) / Eli Lilly, EMD Serono
Preclinical, Journal: Photodynamic Priming Improves the Anti-Migratory Activity of Prostaglandin E Receptor 4 Antagonist in Cancer Cells In Vitro. (Pubmed Central) - Nov 17, 2021
Immunoblotting data identify co-inhibition of EGFR, cAMP-response element binding protein (CREB), and extracellular signal-regulated kinase 1/2 (ERK1/2) as key in the signaling cascades modulated by the combination of EGFR-targeted PDP and EP4 inhibition. This study provides valuable insights into the development of a molecular-targeted photochemical strategy to improve the anti-metastatic effects of EP4 receptor antagonists.
- |||||||||| Clinical, Journal, Combination therapy: Enhanced Immunotherapeutic Efficacy of Anti-PD-L1 Antibody in Combination with an EP4 Antagonist. (Pubmed Central) - Nov 11, 2021
Finally, we show that the dual blockade decreases tumor volume and prolongs survival in mice inoculated with the murine lymphoma cell line EG7. Altogether, these results suggest that TNF-α induced by anti-PD-L1 Ab treatment is associated with T cell dysfunction via PGE/EP4 pathway and that the dual blockade of PD-L1 and EP4 should be considered as a novel immunotherapy for cancer.
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