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Last update 08 May 2025

EGLN2 x PHD2

Last update 08 May 2025

Basic Info

Related Targets

EGLN2PHD2

Drugs associated with EGLN2 x PHD2

ISM-5411

Target

EGLN2 x PHD2

Mechanism

EGLN2 inhibitors [+1]

Active Org.

Insilico Medicine Shanghai Ltd [+1]

Originator Org.

InSilico Medicine Hong Kong Ltd.

Active Indication

Inflammatory Bowel Diseases

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with EGLN2 x PHD2

CTR20241789

/ CompletedPhase 1

一项随机、双盲、安慰剂对照的单次、多次给药剂量递增研究以及食物影响研究以评估ISM5411在中国健康受试者中的安全性、耐受性、药代动力学特征和食物影响

[Translation] A randomized, double-blind, placebo-controlled single-dose, multiple-dose ascending study and food effect study to evaluate the safety, tolerability, pharmacokinetic characteristics and food effect of ISM5411 in healthy Chinese subjects

主要目的：评估ISM5411单次和多次口服给药在中国健康受试者中的安全性和耐受性。次要目的：评估ISM5411单次和多次口服给药后，ISM5411和M15（ISM5411代谢物）在中国健康受试者中的药代动力学（Pharmacokinetics，PK）特征。评估食物在中国健康受试者单次服用ISM5411后，对ISM5411和M15（ISM5411代谢物）PK特性的影响。探索性目的：评估ISM5411单次和多次口服给药后，中国健康受试者外周血生物标志物（促红细胞生成素和血管内皮生长因子）和粪便生物标志物（钙卫蛋白和脂质运载蛋白-2）的表达变化。

[Translation]

Primary objectives: To evaluate the safety and tolerability of single and multiple oral administration of ISM5411 in healthy Chinese subjects. Secondary objectives: To evaluate the pharmacokinetic (PK) characteristics of ISM5411 and M15 (metabolite of ISM5411) in healthy Chinese subjects after single and multiple oral administration of ISM5411. To evaluate the effect of food on the PK characteristics of ISM5411 and M15 (metabolite of ISM5411) after a single dose of ISM5411 in healthy Chinese subjects. Exploratory objectives: To evaluate the changes in the expression of peripheral blood biomarkers (erythropoietin and vascular endothelial growth factor) and fecal biomarkers (calprotectin and lipocalin-2) in healthy Chinese subjects after single and multiple oral administration of ISM5411.

Start Date26 May 2024

Sponsor / Collaborator

Insilico Medicine Shanghai Ltd

NCT06012578

/ CompletedPhase 1

A Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Ascending Dose and Food Effect Study to Evaluate Safety, Tolerability, Pharmacokinetics and Food Effect of ISM5411 in Healthy Subjects

The goal of this clinical trial is to learn about ISM5411 in healthy subjects. The primary objective is to evaluate the safety and tolerability of single and multiple oral doses of ISM5411 in healthy subjects.

Start Date08 Nov 2023

Sponsor / Collaborator

InSilico Medicine Hong Kong Ltd.

100 Clinical Results associated with EGLN2 x PHD2

100 Translational Medicine associated with EGLN2 x PHD2

0 Patents (Medical) associated with EGLN2 x PHD2

182

Literatures (Medical) associated with EGLN2 x PHD2

01 Apr 2025·Journal of Thrombosis and Haemostasis

Therapeutic potential of roxadustat in immune thrombocytopenia: a Mendelian randomization analysis

Article

Author: Meng, Jinxi ; Dong, Shuyue ; Cheng, Xiaoling ; Lin, Zheyan ; Chen, Zhenping ; Wang, Zhifa ; Hu, Yu ; Ouyang, Juntao ; Ma, Jingyao ; Wu, Runhui

BACKGROUNDImmune thrombocytopenia (ITP) is characterized by immune-mediated platelet destruction and impaired megakaryocyte maturation. Hypoxia-inducible factor-1α (HIF-1α), pivotal in the development of megakaryocytes and immune regulation, is downregulated in ITP. Roxadustat, which stabilizes HIF-1α, has emerged as a potential therapeutic drug for ITP that acts by enhancing HIF-1α-mediated megakaryocyte development and modulating immune responses.OBJECTIVESThis study evaluates the safety profile of roxadustat and its therapeutic efficacy for ITP treatment using Mendelian randomization (MR) analysis.METHODSWe used expression quantitative trait loci data for roxadustat's target genes (EGLN1, EGLN2, and EGLN3) and genetic associations with ITP and adverse outcomes from the Open Genome-Wide Association Study project. MR analysis included inverse-variance weighted, MR-Egger regression, weighted median, and MR pleiotropy residual sum and outlier methods to evaluate pleiotropy. Heterogeneity was assessed using Cochran's Q statistic and I² measure with sensitivity analyses. A meta-analysis was performed to integrate effect sizes from multiple literature sources.RESULTSMR analysis revealed a significant association between roxadustat and reduced ITP risk (odds ratio, 0.79; 95% CI, 0.66-0.95; P = .01) with no evidence of horizontal pleiotropy. Meta-analysis confirmed the protective effect of roxadustat on ITP. Utilizing the expression quantitative trait loci of roxadustat's target gene EGLN1 as instrumental variables, an MR analysis of 39 potential adverse reactions revealed no significant increase, suggesting a favorable safety profile for roxadustat.CONCLUSIONRoxadustat demonstrates a potential protective effect against ITP without increasing the risk of adverse outcomes, suggesting its promise as a therapeutic option for ITP and warranting further investigation.

03 Feb 2025·Journal of Clinical Investigation

Postischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis

Article

Author: Schonfeld, Michael ; David, Valentin ; O'Sullivan, James ; Chandel, Navdeep S ; Schipma, Matthew J ; Zhou, Yalu ; An, Si Young ; Rajendran, Ganeshkumar ; Kapitsinou, Pinelopi P ; Thomson, Benjamin R ; Thorp, Edward B ; Sharma, Rajni ; Borkowski, Gabriella S ; Tiwari, Ratnakar ; Courbon, Guillaume ; Quaggin, Susan E

Ischemic acute kidney injury (AKI) is common in hospitalized patients and increases the risk for chronic kidney disease (CKD). Impaired endothelial cell (EC) functions are thought to contribute in AKI to CKD transition, but the underlying mechanisms remain unclear. Here, we identify a critical role for endothelial oxygen sensing prolyl hydroxylase domain (PHD) enzymes 1-3 in regulating postischemic kidney repair. In renal endothelium, we observed compartment-specific differences in the expression of the 3 PHD isoforms in both mice and humans. Postischemic concurrent inactivation of endothelial PHD1, PHD2, and PHD3 but not PHD2 alone promoted maladaptive kidney repair characterized by exacerbated tissue injury, fibrosis, and inflammation. scRNA-Seq analysis of the postischemic endothelial PHD1, PHD2, and PHD3-deficient (PHDTiEC) kidney revealed an endothelial hypoxia and glycolysis-related gene signature, also observed in human kidneys with severe AKI. This metabolic program was coupled to upregulation of the SLC16A3 gene encoding the lactate exporter monocarboxylate transporter 4 (MCT4). Strikingly, treatment with the MCT4 inhibitor syrosingopine restored adaptive kidney repair in PHDTiEC mice. Mechanistically, MCT4 inhibition suppressed proinflammatory EC activation, reducing monocyte-EC interaction. Our findings suggest avenues for halting AKI to CKD transition based on selectively targeting the endothelial hypoxia-driven glycolysis/MCT4 axis.

01 Jan 2025·The Journal of Toxicological Sciences

Prolyl hydroxylase domain enzymes (isoforms 1-3, PHD1-3), but not factor-inhibiting HIF-1 (FIH-1), interact with the IKK complex and attenuate LPS-activated NF-kappa-B

Article

Author: Kitayama, Koji ; Tamura, Akiyoshi ; Imaoka, Susumu ; Oguro, Ami ; Hashimoto, Kentaro ; Adachi, Mutsumi

Hypoxia induces the expression of nuclear factor kappa B (NF-kappa-B). NF-kappa-B functions by forming dimers from five main subunits: p65 (RelA), RelB, p52, p50, and c-Rel. In the classical pathway, NF-kappa-B activity is regulated by the degradation-inducing factor I kappa B kinase (IKK). IKK is composed of an α/β isomer and essential modulator NEMO (γ) subunits in the classical pathway, which may be the major pathway for NF-kappa-B signaling. In the present study, we focused on factor-inhibiting HIF-1 (FIH-1) and Prolyl hydroxylase domain enzyme (PHD), which have been identified as oxygen concentration-dependent regulators of HIF-1α. PHD has three isoforms: PHD1, PHD2, and PHD3, which have different affinities towards HIF-1α. We examined the interactions between IKKα/β and PHD1-3 by immunoprecipitation. PHDs efficiently interacted with IKKα/β. Furthermore, the overexpression of PHDs decreased the mRNA level of IL-1β, a downstream factor of NF-kappa-B activated by LPS. The overexpression of PHD1 and PHD2 markedly reduced IKKα/β protein levels; however, the effects of PHD3 were weaker than those of PHD1 and PHD2. Mutants of the active sites of PHD1 and PHD2 did not decrease IKKα/β protein levels, and a mutation in the active site of PHD3 did not affect IKKα/β protein levels. We also attempted to investigate the interactions of FIH-1 with IKKα/β and IκBα by immunoprecipitation, but found none. Moreover, IKKα/β and p65 protein levels were not affected by the overexpression of FIH-1. Collectively, these results suggest that PHDs directly regulated IKK protein levels, while FIH-1 did not affect the NF-kappa-B classical pathway.

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