Dataset Information

Structure-Activity Relationships and Transcriptomic Analysis of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors.

ABSTRACT: To evaluate the differences in action of commercially available 2-oxoglutarate mimetics and "branched-tail" oxyquinoline inhibitors of hypoxia-inducible factor prolyl hydroxylase (HIF PHD), the inhibitors' IC50 values in the activation of HIF1 ODD-luciferase reporter were selected for comparative transcriptomics. Structure-activity relationship and computer modeling for the oxyquinoline series of inhibitors led to the identification of novel inhibitors, which were an order of magnitude more active in the reporter assay than roxadustat and vadadustat. Unexpectedly, 2-methyl-substitution in the oxyquinoline core of the best HIF PHD inhibitor was found to be active in the reporter assay and almost equally effective in the pretreatment paradigm of the oxygen-glucose deprivation in vitro model. Comparative transcriptomic analysis of the signaling pathways induced by HIF PHD inhibitors showed high potency of the two novel oxyquinoline inhibitors (#4896-3249 and #5704-0720) at 2 μM concentrations matching the effect of 30 μM roxadustat and 500 μM dimethyl oxalyl glycine in inducing HIF1 and HIF2-linked pathways. The two oxyquinoline inhibitors exerted the same activation of HIF-triggered glycolytic pathways but opposite effects on signaling pathways linked to alternative substrates of HIF PHD 1 and 3, such as p53, NF-κB, and ATF4. This finding can be interpreted as the specificity of the 2-methyl-substitute variant for HIF PHD2.

SUBMITTER: Poloznikov AA

PROVIDER: S-EPMC8868400 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Structure-Activity Relationships and Transcriptomic Analysis of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors.

Poloznikov Andrey A AA Nikulin Sergey V SV Hushpulian Dmitry M DM Khristichenko Anna Yu AY Osipyants Andrey I AI Asachenko Andrey F AF Shurupova Olga V OV Savin Svyatoslav S SS Lee Sue H SH Gaisina Irina N IN Thatcher Gregory R J GRJ Narciso Anthony A Chang Eric P EP Kazakov Sergey V SV Krucher Nancy N Tishkov Vladimir I VI Thomas Bobby B Gazaryan Irina G IG

Antioxidants (Basel, Switzerland) 20220124 2

To evaluate the differences in action of commercially available 2-oxoglutarate mimetics and "branched-tail" oxyquinoline inhibitors of hypoxia-inducible factor prolyl hydroxylase (HIF PHD), the inhibitors' IC<sub>50</sub> values in the activation of HIF1 ODD-luciferase reporter were selected for comparative transcriptomics. Structure-activity relationship and computer modeling for the oxyquinoline series of inhibitors led to the identification of novel inhibitors, which were an order of magnitud ...[more]

PMID: 35204103

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Project description:BackgroundFive types of HIF-PHIs have been authorized for anemia treatment in CKD patients in China and Japan. These are enarodustat, roxadustat, daprodustat, vadadustat, and molidustat. How effectively they compare to ESAs about clinical results in CKD-DD patients is uncertain. This study examined the RCT evidence about the benefits and risks of HIF-PHIs and ESAs in dialysis CKD patients.MethodsWe conducted an extensive investigation and network meta-analysis of RCTs. In these RCTs, patients with CKD-DD received one of five different HIF-PHI or ESAs, a placebo, and no medical intervention. Outcomes included hemoglobin, iron parameters, and adverse events, and there were four weeks of follow-up at least. A frequentist framework for multivariate random effects meta-analyzed the results. The effect sizes of categorical variables were displayed as odds ratios. Mean differences were employed for computing continuous outcomes with common units; otherwise, standardized mean differences were applied. The Cochrane tool evaluated the bias risk in RCTs.Results26 RCTs with 14945 patients were qualified for inclusion. Compared to the placebo, HIF-PHIs and ESAs dramatically boosted hemoglobin without affecting serum iron. Roxadustat performed better hemoglobin levels than ESAs (MD 0.32, 95% CI 0.10 to 0.53) and daprodustat (0.46, 0.09 to 0.84). Roxadustat (91.8%) was the top hemoglobin treatment among all medical interventions, as determined by the SUCRA ranking. However, roxadustat caused more thrombosis and hypertension than ESAs (1.61, 1.22 to 2.12) and vadadustat (1.36, 1.01 to 1.82). The lowest rates of hypertension and thrombosis were seen in molidustat (80.7%) and ESAs (88.5%). Compared with a placebo, ESAs and HIF-PHIs all affected TSAT levels. Except for molidustat, the other four HIF-PHIs impact different iron parameters. Regarding ferritin reduction, roxadustat (90.9%) and daprodustat (60.9%) came out on top. Enarodustat (80.9%) and roxadustat (74%) placed best and second in lowering hepcidin levels. The former two medicines for TIBC improvement were vadadustat (98.7%) and enarodustat (80.9%).ConclusionThe most effective treatment for hemoglobin correction is roxadustat. The superior efficacy of reducing hepcidin makes roxadustat and enarodustat appropriate for patients with inflammation. However, the increased risk of hypertension and thrombosis associated with roxadustat should be noted. In patients at risk for hypertension and thrombosis, molidustat and ESAs may be preferable options. When administering roxadustat and daprodustat, clinicians should check ferritin to assess iron storage. Lower TSAT in patients receiving HIF-PHIs and ESAs treatment suggests intravenous iron supplements are needed.

Dataset Information

Structure-Activity Relationships and Transcriptomic Analysis of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors.

Publications

Structure-Activity Relationships and Transcriptomic Analysis of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors.

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