更新于：2023-09-06

FG-2216

更新于：2023-09-06

概要

研发状态

概要

基本信息

药物类型

小分子化药

别名

(((1-Chloro-4-hydroxyisoquinolin-3-yl)carbonyl)amino)acetic acid、1-Chloro-N- (hydroxyformylmethyl-4-hydroxyisoquinoline-3-carboxamide、1-Chloro-N-(hydroxyformylmethyl-4-hydroxyisoquinoline-3-carboxamide

+ [3]

靶点

HIF-1α + PHD2(缺氧诱导因子-1α)

作用机制

HIF-1α抑制剂(缺氧诱导因子-1α抑制剂)、PHD2抑制剂(egl-9 family hypoxia inducible factor 1 inhibitors)

治疗领域

血液及淋巴系统疾病

在研适应症-

非在研适应症

贫血

原研机构

Astellas Pharma, Inc.

在研机构-

非在研机构

Astellas Pharma, Inc.

最高研发状态(全球)终止临床2期

首次获批日期(全球)-

最高研发状态(中国)-

特殊审评-

结构

分子式C12H9ClN2O4

InChIKeyOUQVKRKGTAUJQA-UHFFFAOYSA-N

CAS号223387-75-5

关联

项与 FG-2216 相关的临床试验

NCT00456053 / Completed临床2期

A Randomized Study of the Safety and Efficacy of FG-2216 in Subjects With Renal Anemia Not Requiring Dialysis and Not Receiving Recombinant Human Erythropoietin

The purpose of this study is to test the safety and efficacy of FG-2216 in the treatment of patients with renal anemia who are not receiving erythropoietin and who are not on dialysis.

开始日期2005-12-01

申办/合作机构

FibroGen, Inc.

100 项与 FG-2216 相关的专利（医药）

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项与 FG-2216 相关的文献（医药）

2023-01-01·Frontiers in physiology

No benefit of HIF prolyl hydroxylase inhibition for hypertensive renal damage in renovascular hypertensive rats.

Article

作者: Andrea Hartner ; Thomas Dambietz ; Nada Cordasic ; Carsten Willam ; Nicolai Burzlaff ; Martin Brötsch ; Christoph Daniel ; Mario Schiffer ; Kerstin Amann ; Roland Veelken ; Gunnar Schley ; Karl F Hilgers

Introduction: We previously reported that malignant hypertension is associated with impaired capillary density of target organs. Here, we tested the hypothesis that stabilization of hypoxia-inducible factor (HIF) in a modified "preconditioning" approach prevents the development of malignant hypertension. To stabilize HIF, we employed pharmacological inhibition of HIF prolyl hydroxylases (PHD), that profoundly affect HIF metabolism. Methods: Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats; controls were sham operated. 2K1C rats received either intermittent injections of the PHD inhibitor ICA (2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate) or placebo. Thirty-five days after clipping, the frequency of malignant hypertension was assessed (based on weight loss and the occurrence of characteristic vascular lesions). In addition, kidney injury was compared between all ICA treated versus all placebo treated 2K1C, regardless of the occurrence of malignant hypertension. HIF stabilization was evaluated by immunohistochemistry, and HIF target gene expression by RT-PCR. Results: Blood pressure was elevated to the same degree in ICA- and placebo-treated 2K1C compared to control rats. ICA treatment did not affect the frequency of malignant hypertension or the extent of kidney tissue fibrosis, inflammation, or capillary density. There was a trend towards higher mortality and worse kidney function in ICA-treated 2K1C rats. ICA increased the number of HIF-1α-positive renal tubular cell nuclei and induced several HIF-1 target genes. In contrast, expression of HIF-2α protein as well as HIF-2 target genes were markedly enhanced by 2K1C hypertension, irrespective of ICA treatment. Discussion: We conclude that intermittent PHD inhibition did not ameliorate severe renovascular hypertension in rats. We speculate that the unexpected strong renal accumulation of HIF-2α in renovascular hypertension, which could not be further augmented by ICA, may contribute to the lack of a benefit from PHD inhibition.

2022-05-13·Life sciences3区 · 医学

Identification of EPZ004777 and FG2216 as inhibitors of TGF-β1 induced Treg cells by screening a library of epigenetic compounds.

3区 · 医学

Article

作者: Kavitha Premkumar ; Bhavani S Shankar

AIMS:

Regulatory T cells play an essential role in immune tolerance and homeostasis. Their long-term stability depends on epigenetic modifications and identification of small molecule modulators of Treg differentiation therefore has many applications. In this study, we performed a novel functional screen of an epigenetic compound library to identify compounds that can modulate generation of TGF-β1 induced T regulatory cells.

MAIN METHODS:

A screening strategy based on IFN-γ ELISA was designed to screen epigenetic compound library. Effect of hit compounds on Treg phenotype and function was assessed by RT-PCR, flow cytometry and suppression assays. TGF-β signalling proteins were assayed by western blotting. Chromatin Immunoprecipitation (ChIP) assay was used to assess epigenetic modifications at Foxp3 gene locus.

KEY FINDINGS:

We screened 160 compounds to identify hits capable of reversing TGF-β induced inhibition of IFN-γ production in activated spleen cells and CD4⁺ T cells. Two compounds EPZ004777 and FG-2216 consistently reversed TGF-β1 iTregs in terms of (a) differentiation of naïve T cells into CD4⁺CD25⁺Foxp3⁺Treg cells, (b) Foxp3 target gene expression and (c) Treg suppressive function without affecting TGF-β downstream signalling. ChIP assay revealed that the compounds were able to reverse - TGF- β mediated decrease in epigenetic marks H3K27me3 and 5-mC and an increase in epigenetic marks H3K4me3 and H3K27Ac in the promoter and conserved non coding sequence (CNS1) regions of the Foxp3 gene.

SIGNIFICANCE:

EPZ004777 and FG-2216 have been identified as potent epigenetic modulators that can reverse TGF-β1 induced T regulatory cells and may be used to treat diverse immune disorders.

2021-10-22·Analytical chemistry1区 · 化学

Sensing an Oxygen Sensor: Development and Application of Activity-Based Assays Directly Monitoring HIF Heterodimerization.

1区 · 化学

Article

作者: Liesl K Janssens ; Christophe P Stove

Conventionally, hypoxia-inducible factor (HIF) activation by prolyl hydroxylase domain enzyme (PHD) inhibition is monitored by gene reporter assays. The principle relies on the monitoring of an upstream event (HIF stabilization) by the downstream transcriptional activity. Here, we developed a novel approach to directly sense HIF activation by monitoring the heterodimerization of the HIFα/HIFβ subunits, constituting the functional HIF transcription factor. Two live cell-based biosensor assay setups were designed, utilizing functional complementation of split-nanoluciferase as a tool to measure HIFα/HIFβ protein-protein interaction resulting from the stabilization of HIF1α or HIF2α. The assay setup in a 96-well format was optimized for a duration of 2 h, and a HEK293T transfection protocol was introduced for the optimal configuration of HIFα/HIFβ-fusion proteins. These new bioassays outperformed hypoxia response element-based gene reporter assay, the current state-of-the-art assay, in terms of sensitivity. Applicability was demonstrated using a panel of PHD inhibitors, including roxadustat, molidustat, daprodustat, desidustat, vadadustat, and FG-2216, for which concentration-response curves were generated, allowing for the derivation of potency (EC₅₀) and efficacy (E_max) data. The broad applicability of the biosensors was established via applying hypoxia mimetic CoCl₂, iron chelator desferrioxamine, proteasome inhibitor MG-132, and 2-OG mimetic dimethyloxalylglycine on the assays, indicating concentration-dependent effects.

项与 FG-2216 相关的新闻（医药）

2006-05-04

·Pharma Times

Astellas in mega deal for oral EPO rivals

Japanese drugmaker Astellas has licensed exclusive rights to a series of anaemia drugs from FibroGen, in a deal that could eventually bring in up to $2 billion to the US firm in the coming years. Astellas had previously licensed Japanese rights to the drugs, known as hypoxia-inducible factor prolyl hydroxylase inhibitors, but in the latest agreement has extended its rights to include Europe, the Commonwealth of Independent States, the Middle East and South Africa. The deal includes FG-2216 and FG-4592, which are currently in human clinical trials, with FibroGen retaining rights to compounds in the rest of the world. Under the terms of the agreement, Astellas will pay a licensing fee of $300 million upon signing, milestones totaling $465 million and share in the costs of a transatlantic development programme and patent support. If all forecast sales targets are achieved, FibroGen could receive in excess of $2 billion during the 10 to 15 years after 2010. In addition, Astellas will purchase $50 million worth of shares in the US biotechnology firm. The oral compounds inhibit the enzyme that degrades erythropoietin, and could be a more patient-friendly therapy option for anaemia, which is currently treated with injectable recombinant forms of EPO such as Amgen’s Epogen (epoetin alfa) and Aranesp (darbepoetin alfa), as well as Roche’s NeoRecormon (epoetin beta). Together these drugs account for a multibillion dollar market worldwide. For example, in Europe, sales of EPO products for anaemia of chronic kidney disease and chemotherapy-induced anaemia total approximately $3 billion a year. Astellas noted that oral treatments to stimulate red blood cell production could address larger, multi-million patient market opportunities currently not penetrated by EPO products, including chronic kidney disease in patients not yet on dialysis and anaemias caused by cancer, congestive heart failure, advancing age and chronic disease. Sales potential Astellas said it plans to start marketing the agents in 2011-2012, and predicts that the drugs have an annual sales potential in Europe of around 50 billion yen (roughly $450 million), which could double at peak. A launch in Japan should occur a little later, and Astellas said the market potential there is in the region of 30-50 billion yen.