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更新于：2025-05-07

EP4 x EP2 x DP1

更新于：2025-05-07

基本信息

关联

项与 EP4 x EP2 x DP1 相关的药物

OKN-4395

靶点

DP1 x EP2 x EP4

作用机制

DP1抑制剂 [+2]

在研机构

Nanjing Epkin Biotechnology Co., Ltd. [+1]

原研机构

Owkin, Inc.

在研适应症

晚期恶性实体瘤 [+8]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 EP4 x EP2 x DP1 相关的临床试验

NCT06789172

/ Recruiting临床1期

A Phase 1, Open-label, Multicenter, Dose-escalation and Cohort Expansion Study of OKN4395, a Triple Antagonist of EP2, EP4, and DP1 Prostanoid Receptors, as Monotherapy and in Combination With Pembrolizumab, in Patients With Advanced Solid Tumors

The purpose of this study is to investigate the study drug, OKN4395, administered alone and in combination with pembrolizumab.
The overall objectives of this study are to determine the safety and tolerability (degree to which side effects of a drug can be tolerated) of OKN4395 alone and in combination with pembrolizumab, OKN4395 and metabolites (broken-down substances) of OKN4395 levels in the blood, and antitumor activity of OKN4395 alone and in combination with pembrolizumab.
This study will be split into 2 parts. Part 1a will look at multiple doses of OKN4395 either alone (monotherapy) or with pembrolizumab (combination therapy) administered on day 1 of each 21-day cycle in patients with solid tumors until the participant has disease progression or discontinues for any reason. The dose of OKN4395 will be increased, after each group of 3 or more patients completes their first 3 weeks of treatment and their data is evaluated for safety, with a planned dose range from 10 mg twice a day to 450 mg twice a day through 13 dose levels. Part 1b will evaluate OKN4395 alone and in combination with pembrolizumab administered on day 1 of each 21-day cycle in patients with selected cancer types. Part 1b will comprise 5 cohorts: Cohort 1 in sarcoma (OKN4395 alone), Cohort 2 pancreatic adenocarcinoma (OKN4395 alone), Cohort 3 in non-small cell lung cancer (NSCLC), Cohort 4 in colorectal cancer, and Cohort 5 in head & neck squamous cell carcinoma (HNSCC), with cohorts 3 to 5 in combination with pembrolizumab. The monotherapy expansion Cohort 1 will also be used to explore the effect of food on the levels of OKN4395 in the blood. Similarly, Cohort 2 will be used to explore the effect of gastric pH on the levels of OKN4395 in the blood.
The overall study will enrol approximately 166 participants with up to 54 participants to receive OKN4395 alone and 12 participants to receive OKN4395 in combination with pembrolizumab in Part 1a, and 100 participants in Part 1b split: 40 on monotherapy and 60 on combination therapy. The study will be conducted in the US, Australia, UK and in the EU.

开始日期2025-01-23

申办/合作机构

Nanjing Epkin Biotechnology Co., Ltd.

[+1]

100 项与 EP4 x EP2 x DP1 相关的临床结果

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100 项与 EP4 x EP2 x DP1 相关的转化医学

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0 项与 EP4 x EP2 x DP1 相关的专利（医药）

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项与 EP4 x EP2 x DP1 相关的文献（医药）

2025-06-01·Schizophrenia Research

Developing a risk assessment model for treatment-resistant schizophrenia: The role of niacin receptor GPR109A and prostaglandin receptors DP1, EP2, and EP4 in the niacin-induced flushing pathway

Article

作者: Chen, Bao-Yu ; Lin, Jin-Jia ; Huang, Chih-Chun ; Lin, Sheng-Hsiang ; Yao, Chi-Yu ; Chiu, Chi-Wei ; Chen, Po-See ; Chang, Wei-Hung ; Jang, Fong-Lin ; Tseng, Huai-Hsuan ; Wang, Tzu-Yun

Schizophrenia patients show attenuated niacin flush responses compared to healthy controls (HC) attributed to abnormalities in the niacin-induced flushing pathway. Underlying immunological abnormalities may reduce the niacin receptor GPR109A's response and implicated in treatment-resistant schizophrenia (TRS). This pathway involves GPR109A and the downstream vasodilatory prostaglandins (PGs), PGD₂ and PGE₂, along with their receptors DP₁, EP₂, and EP₄, contributing to vasodilation and neuroprotection. We hypothesized that the niacin receptor GPR109A, PGs, and their receptors play a significant role in the pathogenesis of TRS. We aimed to investigate GPR109A, DP₁, PGD₂, PGE₂, EP₂, and EP₄ as potential biomarkers for identifying TRS and construct a risk assessment model for TRS. We recruited 58 TRS, 67 NTRS patients, and 115 HC. We observed significant differences in niacin flush responses and expression levels of GPR109A, PGE₂, DP₁, EP₂, and EP₄ between the schizophrenia and HC groups. TRS group exhibited lower expression levels of GPR109A, DP₁, EP₂, and EP₄ than NTRS group. Receiver operating characteristic curve analysis combining the six markers for schizophrenia versus HC yielded an area under the curve (AUC) of 0.98, whereas an analysis combining the four markers for TRS versus NTRS yielded an AUC of 0.91. Niacin-induced flushing signaling cascade enrichment is linked to the intensity of the inflammatory response, with associated mediators and their receptor affinities potentially regulating pharmacological effects. These findings suggest that the niacin receptor GPR109A and PG receptors DP₁, EP₂, and EP₄, which are involved in the niacin-induced flushing pathway, may serve as biomarkers for predicting TRS.

2021-04-01·YAKUGAKU ZASSHI4区 · 医学

Activation Mechanism of Prostanoid Receptors —X-ray Crystallography of EP3 Receptor—

4区 · 医学

Review

作者: Morimoto, Kazushi

Prostanoids [prostaglandins (PGs) and thromboxanes (TXs)] are a series of bioactive lipid metabolites that function in an autacoid manner via activation of cognate G protein-coupled receptors (GPCRs). The nine subtypes of prostanoid receptors (DP1, DP2, EP1, EP2, EP3, EP4, FP, IP, TP) are involved in a wide range of functions, including inflammation, immune response, reproduction, and homeostasis of the intestinal mucosa and cardiovascular system. Among the prostanoid receptors, the structure of antagonist-bound DP2, which belongs to the chemoattractant receptor family, was previously determined. However, the mechanisms of prostanoid recognition and receptor activation remained elusive. To address this issue, we determined the crystal structures of antagonist-bound EP4 and PGE₂-bound EP3. The EP3-PGE₂ complex exhibits an active-like conformation, including outward movement of the cytoplasmic end of transmembrane (TM) 6 relative to the cytoplasmic end of TM6 of the EP4 complex. The carboxyl moiety of PGE₂ is recognized through three hydrogen bonds formed by highly conserved residues: Y114^_2.65, T206^{Extracelluar loop 2 (ECL2)}, and R333^7.40 (superscripts denote Ballesteros-Weinstein numbering). In addition, the ω-chain of PGE₂ orients toward TM6, which appears to contribute to receptor activation. The structure reveals important insights into the activation mechanism of prostanoid receptors and provides a molecular basis for the binding modes of endogenous ligands. These findings should facilitate the development of subtype-selective and non-PG-like ligands.

2015-12-01·Behavioral and Brain Functions2区 · 心理学

Hippocampal neuronal cyclooxygenase-2 downstream signaling imbalance in a rat model of chronic aluminium gluconate administration

2区 · 心理学

ArticleOA

作者: Yang, Junqing ; Ye, Mengliang ; Wang, Jianfeng ; Yu, Lijuan ; Lei, Wenjuan ; Guo, Yuanxin ; Wang, Hong

BACKGROUNDAcute and chronic brain damages including neurodegenerative diseases are a group of neuroinflammation-associated diseases characterized by cognitive function defect and progressive neuron loss. The pathophysiological procession of brain damages involves the overexpression of cyclooxygenase (COX)-2. Owing to the limited benefit to chronic brain damage and the late adverse effect of COX-2 inhibitors, the COX downstream signaling pathway has become a focus in neurological research. In order to explore the mechanism of aluminum neurotoxicity and the importance of COX2 downstream signaling pathways to chronic brain damage, the present study was designed to simultaneously observe the prostaglandin (PG) contents, and the expressions of PG synthases and PG receptors of hippocampus in a rat model induced by chronic administration of aluminium gluconate.METHODSA rat model of chronic brain damage was established by chronic intragastric administration of aluminium gluconate (Al3+ 200 mg/kg per day, 5d a week for 20 weeks). PG contents, the expressions of PG synthases, and the expressions of PG receptors in rats were measured by ELISA, RT-PCR and Western blotting, respectively.RESULTSChronic aluminium gluconate administration resulted in hippocampal neuron injury and learning and memory disorders in rats. Aluminium gluconate administration also resulted in increased levels of PGE2, PGD2, TXA2, PGI2, and PGF2α in rat hippocampus. The DP1, EP2, IP, mPGES-1, EP4, PGIS and TXAS mRNA expressions, and the DP1, EP2 and IP protein expressions significantly increased in the Al-treated hippocampus, while the EP3 and FP mRNA and protein expressions and the TP mRNA expression decreased.CONCLUSIONSThe PGS/PGs/PG receptors signaling pathway in chronic aluminium gluconate-overloaded rat hippocampus is disturbed, which may be involved in the mechanism of aluminium neurotoxicity.

项与 EP4 x EP2 x DP1 相关的新闻（医药）

2025-01-31

·PipelineReview

Owkin Announces First Patient Dosed in Phase I AI-optimized Clinical Trial of OKN4395, a First-in-Class EP2/EP4/DP1 Triple Inhibitor for Patients with Solid Tumors

PARIS, France I January 30, 2025 I Owkin , the first end-to-end AI-biotech that uses agentic AI to revolutionize drug discovery, development, and diagnostics, today announced that the first patient has been dosed in its Phase I clinical trial of OKN4395 on January 22, 2025. OKN4395 builds upon well-characterized EP2/EP4 inhibition, through a newly identified and equipotent inhibition of DP1. The clinical significance of this first-in-class triple inhibition is being evaluated in this trial. AI-optimized study design Owkin’s proprietary K1.0 Operating System was instrumental in advancing OKN4395 from asset selection through to clinical development. By building a detailed biological understanding of the EP2/EP4/DP1 targets and their complex mechanisms of action, Owkin’s AI operating system was used to optimize the clinical development strategy. The program integrates Owkin’s expertise in AI-driven indication selection, external control arms (digital twins) for early anti-tumor activity insights in Phase I, and biomarker-led patient subtyping to enhance the probability of clinical success. Thomas Clozel, MD, CEO & Co-founder of Owkin, said: “OKN4395 reflects not only a decade of discovery efforts by Idorsia and its collaborators but also exemplifies the transformative power of Owkin’s K1.0 Operating System. This milestone underscores our ability to rapidly translate a promising asset into an AI-optimized clinical program.” A first-in-class asset: OKN4395 Prostaglandins E 2 and D 2 (or PGE 2 , PGD 2 ) are hormone-like molecules produced naturally in the body, and are the natural ligands for prostanoid receptors EP2, EP4, and DP1, respectively. The PGE 2 /EP2/EP4 and PGD 2 /DP1 pathways are both known to be immunosuppressive 1,2 . Well-described in oncology, hyperactivity of the PGE 2 /EP2/EP4 pathway in certain cancers allows them to avoid the immune system’s effector mechanisms, leading to progression and resistance through tumor growth or metastasis 1 . OKN4395 is the first compound in the clinic to selectively inhibit EP2, EP4, and DP1 receptors. This novel mechanism offers the potential to restore immune function, providing transformative treatment options for patients with advanced solid tumors. The INVOKE Study (OKN-4395-121) INVOKE is a global, multicenter, Phase Ia/1b, first-in-human, open-label trial evaluating OKN4395 in patients with advanced solid tumors. Phase Ia primarily assesses safety and tolerability through dose escalation of OKN4395 as both a monotherapy and in combination with pembrolizumab. Phase Ib will expand into a further four cohorts, and assess preliminary anti-tumor activity, as well as safety and extensive exploratory analyses. References SOURCE: Owkin

临床1期