AI Article Synopsis
- The study highlights a new strategy for treating anemia in chronic kidney disease by stabilizing the hypoxia-inducible factor (HIF) through the inhibition of prolyl hydroxylase domain enzymes (PHDs).
- Using structure-based drug design (SBDD) and generative models, researchers developed a novel compound that effectively inhibits PHD, unlike previous carboxylic acid inhibitors.
- This compound shows promising characteristics such as good solubility, low risk of drug interactions, and effective results in reducing anemia when administered orally in a rat model.
Article Abstract
Stabilization of hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase domain enzymes (PHDs) represents a breakthrough in treating anemia associated with chronic kidney disease. Here, we identified a novel scaffold for noncarboxylic PHD inhibitors by utilizing structure-based drug design (SBDD) and generative models. Iterative optimization of potency and solubility resulted in compound which potently inhibits PHD thus stabilizing HIF-α . X-ray cocrystal structure confirmed the binding model was distinct from previously reported carboxylic acid PHD inhibitors by pushing away the R383 and Y303 residues resulting in a larger inner subpocket. Furthermore, compound demonstrated a favorable / absorption, distribution, metabolism, and excretion (ADME) profile, low drug-drug interaction risk, and clean early safety profiling. Functionally, oral administration of compound at 10 mg/kg every day (QD) mitigated anemia in a 5/6 nephrectomy rat disease model.
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| http://dx.doi.org/10.1021/acs.jmedchem.3c01932 | DOI Listing |
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