An Open-Label Study to Evaluate the Safety and Efficacy of PRX-08066 in Patients With Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease

A 3-month open label study to evaluate the safety and efficacy of PRX-08066 in patients with pulmonary hypertension and COPD.

开始日期2008-05-01

申办/合作机构

EPIX Pharmaceuticals, Inc.

NCT00345774

/ Completed临床2期

A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Short-Term Efficacy and Safety of PRX-08066 in Patients With Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease

This study is being conducted to see if PRX-08066 can lower pulmonary artery pressures in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease.

开始日期2006-06-01

申办/合作机构

EPIX Pharmaceuticals, Inc.

100 项与 PRX-08066 相关的临床结果

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100 项与 PRX-08066 相关的转化医学

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100 项与 PRX-08066 相关的专利（医药）

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项与 PRX-08066 相关的文献（医药）

2024-11-04·NEURO-ONCOLOGY

Targeting HTR2B suppresses nonfunctioning pituitary adenoma growth and sensitizes cabergoline treatment via inhibiting Gαq/PLC/PKCγ/STAT3 axis

Article

作者: Shaojian Lin ; Changxi Han ; Liangbo Wang ; Yanting Liu ; Ning Huang ; Changsheng Li ; Hong Yao ; Tao Zhang ; Meiqing Lou ; Hao Tang ; Anke Zhang ; Bo Zhang ; Yijun Cheng ; Zhe Bao Wu ; Li Xue ; Yuting Dai ; Yu Wang ; Jing Xie

Abstract:

Background:

Managing nonfunctioning pituitary adenomas (NFPAs) is difficult due to limited drug treatments. Cabergoline’s (CAB) effectiveness for NFPAs is debated. This study explores the role of HTR2B in NFPAs and its therapeutic potential.

Methods:

We conducted screening of bulk RNA-sequencing data to analyze HTR2B expression levels in NFPA samples. In vitro and in vivo experiments were performed to evaluate the effects of HTR2B modulation on tumor growth and cell cycle regulation. Mechanistic insights into the HTR2B-mediated signaling pathway were elucidated using pharmacological inhibitors and molecular interaction assays.

Results:

Elevated HTR2B expression was detected in NFPA samples, which was associated with increased tumor survival. Inhibition of HTR2B activity resulted in the suppression of tumor growth through modulation of the G2M cell cycle. The inhibition of HTR2B with PRX-08066 was found to block STAT3 phosphorylation and nuclear translocation by interfering with the Gαq/PLC/PKC pathway. A direct interaction between PKC-γ and STAT3 was critical for STAT3 activation. CAB was shown to activate pSTAT3 via HTR2B, reducing its therapeutic potential. However, the combination of an HTR2B antagonist with CAB significantly inhibited tumor cell proliferation in HTR2B-expressing pituitary tumor cell lines, a xenografted pituitary tumor model, and patient-derived samples. Analysis of patient-derived data indicated that a distinct molecular pattern characterized by upregulated HTR2B/PKC-γ and downregulated BTG2/GADD45A may benefit from combination treatment with CAB and PRX-08066.

Conclusions:

HTR2B is a potential therapeutic target for NFPAs, and its inhibition could improve CAB efficacy. A dual therapy approach may be beneficial for NFPA patients with high HTR2B expression.

2019-04-01·Neurobiology of aging2区 · 医学

Screening of a neuronal cell model of tau pathology for therapeutic compounds

2区 · 医学

Article

作者: Eckhard Mandelkow ; Christoph Möhl ; Marcus Pickhardt ; Michele Tassoni ; Ana Kitanovic ; Birgit Kurkowsky ; Philip Denner ; Eugenio Fava

We have developed a cell-based phenotypic automated high-content screening approach for N2a cells expressing the pro-aggregant repeat domain of tau protein (tau^RDΔK), which allows analysis of a chemogenomic library of 1649 compounds for their effect on the inhibition or stimulation of intracellular tau aggregation. We identified several inhibitors and stimulators of aggregation and achieved a screening reproducibility >85% for all data. We identified 18 potential inhibitors (= 1.1% of the library) and 10 stimulators (= 0.6% of the library) of tau aggregation in this cell model of tau pathology. The results provide insights into the regulation of cellular tau aggregation and the pathways involved in this process (e.g., involving signaling via p38 mitogen-activated protein kinase, histone deacetylases, vascular endothelial growth factor, rho/ROCK). For example, inhibitors of protein kinases (e.g., p38) can reduce tau aggregation, whereas inhibitors of deacetylases (histone deacetylases) can enhance aggregation. These observations are compatible with reports that phosphorylated or acetylated tau promotes pathology.

2018-05-01·The American journal of pathology2区 · 医学

Effects of 5-Hydroxytryptamine Class 2 Receptor Antagonists on Bronchoconstriction and Pulmonary Remodeling Processes

2区 · 医学

Article

作者: Löfdahl, Anna ; Westergren-Thorsson, Gunilla ; Rydell-Törmänen, Kristina ; Wenglén, Christina ; Larsson-Callerfelt, Anna-Karin

Serotonin [5-hydroxytryptamine (5-HT)] is associated with several chronic pulmonary diseases, recognizing 5-HT₂ receptor antagonists as potential inhibitors of tissue remodeling. However, the effects of 5-HT₂ receptors, especially 5-HT_2B receptors on airway function and remodeling, are unclear. We investigated the role of 5-HT_2B receptors on airway smooth muscle contractility and remodeling processes. Murine precision-cut lung slices were pretreated with 5-HT_2B receptor antagonists (EXT5, EXT9, RS 127445, and PRX 08066), as well as ketanserin (5-HT_2A/2C receptor antagonist) (1, 10 μmol/L), before addition of cumulative concentrations of 5-HT to induce bronchoconstriction. Remodeling effects after treatment with 10 μmol/L 5-HT and 5-HT₂ receptor antagonists were further studied in distal lung tissue by examining release of profibrotic transforming growth factor (TGF)-β1 and proliferation of human bronchial smooth muscle cells (HBSMCs). 5-HT-induced bronchoconstriction was significantly reduced by EXT5, EXT9, and ketanserin, but not by RS 127445 or PRX 08066. The 5-HT_2B receptor antagonists significantly reduced TGF-β1 release. 5-HT, in combination with TGF-β1, increased proliferation of HBSMCs, a process reduced by EXT5 and EXT9. Our results indicate that EXT5 and EXT9 may relieve bronchoconstriction in murine airways and serve as an add-on effect in attenuating pulmonary remodeling by improving airway function. The antiproliferative effect on HBSMCs and the inhibition of TGF-β1 release further support a role of 5-HT_2B receptors in pathologic remodeling processes.

项与 PRX-08066 相关的新闻（医药）

2026-03-12

·科佰生物

5-HTR2 （5-羟色胺受体2）相关细胞模型

5-羟色胺（5-HT），是一种调节情绪、行为和认知的信号传导介质。以往研究更多聚焦于5-HT在中枢神经系统（CNS）中的作用。然而，5-HT也与肿瘤、炎症和病原体感染等病理状态存在密切关联。5-HT参与肿瘤细胞迁移、转移播散及血管生成过程。此外，通过免疫细胞表达的不同5-HT受体（5-HTRs），5-HT还能影响先天性及适应性免疫系统的免疫调节功能。迄今已发现7类5-羟色胺受体（5-HTR），即5-HTR1～5-HTR7，并总计多达16种亚型。其中，5-HT2R可分为5-HTR2A、5-HTR2B、5-HTR2C等受体亚型，并且5-HTR2是药物治疗的重要靶点。 5-HTR2的生物学特性及功能 5-HT2家族包括三种受体；5-HT2A、5-HT2B和5-HT2C具有42-51%的总氨基酸序列同源性，并且可以与Gq/G11偶联以增加肌醇磷酸盐的水解并提高细胞质中Ca2+水平。此外，Gq/G11与其他转导途径（PI3K/Akt和ERK）的偶联是明显的。5-HT2C受体易于进行RNA编辑，导致多种不同的亚型，这些亚型可能显示出改变的转导效率以及优选的转导途径偶联。这种RNA编辑可以通过精神药物进行调节，从而以特定于大脑区域的方式改变这些受体的功能。 5-HT2A受体广泛分布于中枢神经系统（CNS）和外周组织中。在中枢神经系统内，它主要位于富含血清素的区域，包括新皮层、嗅结节、海马和杏仁核，以及边缘和基底神经节结构7。5-HT2A受体在调节认知、情绪和神经可塑性过程中起着关键作用。它在大脑皮层V层锥体神经元的顶端树突上的浓度特别高，能够通过谷氨酸释放调节和与其他受体系统的相互作用来调节工作记忆、注意力和其他执行功能。这种受体对海马和杏仁核功能至关重要，海马和杏仁核是参与学习、记忆形成和情绪处理的关键结构。这两个区域都从中缝核接收密集的5-羟色胺能神经支配，5-HT2A受体激活通过增强空间编码精度、调节GABA等中间神经元介导的抑制、促进记忆巩固过程等过程调节其活性。影响这些过程与神经系统疾病的治疗有关。尽管5-HT2A受体拮抗剂（如氯氮平、哌替嗪）和反向或部分激动剂被广泛用于治疗精神分裂症、认知障碍和偏头痛，但在治疗上使用其激动剂具有挑战性。这种困难是因为受体可以激活不同的效应蛋白，特别是Gq和β-arrestin。Gq主要与受体结合，启动磷脂酶C（PLCβ）的激活，然后导致肌醇三磷酸（IP3）和二酰基甘油（DAG）等次级信使的产生，导致钙释放和蛋白激酶C（PKC）激活12。此外，5-HT2A受体与β-arrestin相互作用，促进受体内化和脱敏，同时也启动不同的细胞内信号级联。这些机制导致不同的生理效应，如抗抑郁药和致幻结果。自1992年首次对5-羟色胺2B受体（5-HTR2B）进行表征以来，5-HTR2B的研究取得了重大进展。有证据表明，5-HTR2B与心血管系统、纤维化疾病、癌症、胃肠道（GI）和神经系统的调节有关。5-HTR2B与不同配体结合为配体识别、激活机制和偏置信号传导提供了很好的见解。目前已经发现并开发了许多5-HT2BR拮抗剂（如 RS-127445、PRX-08066等）。 5-HTR2C是首批测序和克隆的5-HT受体之一。编码5-HTR2C的基因位于人类染色体Xq24上。它含有三个内含子（而不是两个，如5-HTR2A和5-HTR2B），编码一种具有七个跨膜区的蛋白质产物。小鼠、大鼠和人类跨膜区5-HTR2C的同源性超过80%。与外周神经系统相比，5-HTR2C在中枢神经系统（CNS）中广泛表达。在中枢神经系统中，5-HTR2C在这些与能量代谢相关的已知脑区表达，包括腹侧被盖区（VTA）、弓状核（ARC）、孤束核（NTS）、下丘脑室旁核（PVN）和外侧臂旁核（LPBN）。对5-HTR2C功能丧失或获得的遗传研究表明，5-HTR2C在这些脑区维持能量稳态中起着关键作用，已被证明可以调节能量稳态，包括进食和葡萄糖代谢。5-HTR2C的最佳理解功能是通过5-HTR2C在下丘脑的促阿片黑皮质素（POMC）神经元中的作用来调节食物摄入。血清素与5-HTR2C的结合导致异三聚体G蛋白的解离，该蛋白与5-HTR2C的第二个细胞内环结合。解离后，亚基Gα/q11激活磷脂酶C，产生肌醇三磷酸（IP3）和二酰基甘油（DAG），从而激活蛋白激酶C（PKC）。PKC激活细胞外调节激酶（ERK）通路，导致c-Fos磷酸化和POMC合成。POMC被加工成α-黑素细胞刺激激素（α-MSH），通过黑皮质素4受体（MC4Rs）激活PVN中的神经元。PVN神经元的激活诱导饱腹感，即停止进食，这是一种厌食反应。 5-HTR2C是新型减肥药物最有前景的靶点之一。许多靶向5-HT信号传导的调节剂，包括西布曲明（血清素和肾上腺素再摄取抑制剂）、mCPP和芬氟拉明（也称为氟西汀，选择性血清素再摄取抑制剂。）已被用作食欲抑制剂。西布曲明和氟西汀可以在体内增加细胞外血清素水平，非选择性地刺激所有突触后亚型，然后刺激5-HTR2C抑制食物摄入。Heisler报告称，mCPP不会抑制5-HTR2C敲除小鼠的食物摄入，也会削弱芬氟拉明（血清素释放剂和再摄取抑制剂）的吞咽作用，这表明5-HTR2C在d-芬氟拉明诱导饱腹感中起着关键作用。芬氟拉明是一种治疗肥胖症的有效药物，以Pondimin®/Redux®的名义出售，可以降低食欲。芬氟拉明与血清素5-HTR2C结合较弱，d-Fen以高亲和力结合并激活血清素5-HTR2B和5-HTR2C，以中等亲和力结合并活化血清素5-HTR2A（115-117）。然而，芬氟拉明与心脏瓣膜病和肺动脉高压的副作用有关，促使其退出临床使用。 5-HTR2的细胞模型为了助力5-HTR2靶点药物的研发，科佰生物开发了一系列关于5-HTR2的细胞模型，用于候选药物早期机理研究。部分结果如下：货号 5-HTR2A HEK293 CBP71555 5-HTR2B HEK293 CBP71582 5-HTR2C(no edited) HEK293 CBP71598 5-HTR2C(edited) HEK293 CBP71583 5-HTR2B CHO CBP71575 5-HTR2C(no edited) CHO CBP71584 5-HTR2C (edited) CHO CBP71574 5-HTR2A HEK293 CBP71555 Figure 6. HTRF IP-One Assay with 5-HTR2A HEK293(C68). 5-HTR2B HEK293 CBP71582 Figure 7. HTRF IP-One Assay with 5-HTR2B HEK293( C26). 5-HTR2C(no edited) HEK293 CBP71598 Figure 8. HTRF IP-One Assay with 5-HTR2C(no edited) HEK293 HEK293 (C134). 5-HTR2C(edited) HEK293 CBP71583 Figure 9. HTRF IP-One Assay with 5-HTR2C(edited) HEK293 (C38). 5-HTR2B CHO CBP71575 Figure 10. HTRF IP-One Assay with 5-HTR2B CHO( C17). 5-HTR2C(no edited) CHO CBP71584 Figure 11. HTRF IP-One Assay with 5-HTR2C(no edited) CHO(C40). 5-HTR2C (edited) CHO CBP71574 Figure 12. HTRF IP-One Assay with 5-HTR2C(edited) CHO(C57). 药物靶点模型报告基因细胞模型可以很好的反映分子作用机制，同时具备更小的变异性和更好的可操作性，已被中检院及药企广泛应用于抗体药物生物活性的检定，对于药物研发、质量控制、批次放行都有重要意义。科佰生物公司十分重视研发创新，凭借细胞功能改造技术、高精度和灵活的基因编辑工具平台，提供包括激酶，GPCR，免疫治疗，耐药等多类疾病靶点的药物检测细胞模型。目前已覆盖1500多株现货细胞模型，同时提供高质量的Cell-base生物测活服务。免疫治疗靶点细胞模型 ● T Cells Activation Assays (NFAT, IL2, NFκB….) ● Fc Effectors Activity Assays ( ADCC, ADCPs…) ● Immune Checkpoint Bioassays: Co-Inhibitory Targets (PD-1/PD-L1&2, TIGIT/CD155, CTLA4, LAG3, LILRB4/APOE, CD112R/CD112, SIRPα/CD47, TIM-3, BTLA/HVEM, CD161/CLEC2D, TIGIT&PD-1, LAG3&PD-1, CTLA4&PD-1 Combi…) ● Immune Checkpoint Bioassays: Co-Stimulatory Targets (OX40, 4-1BB, GITR, CD27, HVEM/LIGHT, CD28, BTLA…) ● Cytokines and Growth Factor Assays ( BCMA, TGFβ, EGF, CSF1R, IL2, IL15, IL4&13, IL6, IL10, IL11, IL12, IL18, IL23, IL31, IL36, IFNs, OSMR, RANKL, TPO, TIE2, Wnt, EPO, VEGF, TSLP, NGF…) ● Others (TLR family members, STING，A2A family members, SARS Cov2…) -科佰生物产品- 免疫治疗细胞库点击查看 BaF3激酶靶点细胞株点击查看 GPCR细胞库点击查看耐药细胞点击查看 << 滑动查看下一张图片 >> 部分文字，图片来源网络，如涉及侵权，请联系告知。 ●CCL2-CCR2轴在癌症免疫中的作用 ●【限免】解锁肿瘤研究与药物开发新维度：科佰Cell-Panorama细胞全景画像数据库正式上线，两大核心模块全景赋能！ ●信号调控因子NFAT 关注科佰生物了解更多资讯热线电话：4008-750-250 药靶模型联系方式:华东销售经理(上海）：18240630236华东销售经理(上海、江苏、安徽）：15715191010华中&华西销售经理：18071545918华中&西南销售经理：13871580511华北销售经理：18628311252 华南销售经理：13823536064 全国销售经理：13816461235 邮箱：sales@cobioer.com 网站：www.cobioer.com

100 项与 PRX-08066 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	PRX-08066	-	DB05607

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
肺性高血压	临床2期	美国	EPIX Pharmaceuticals, Inc.	2006-06-01
慢性阻塞性肺疾病	临床2期	美国	EPIX Pharmaceuticals, Inc.	2006-06-01
肺动脉高压	临床2期	美国	EPIX Pharmaceuticals, Inc.	2006-06-01
高血压	临床2期	-	Allergan UC	-