ABSTRACT
Plerixafor is a CXCR4 antagonist approved in 2008 by the FDA for hematopoietic stem cell collection. Subsequently, plerixafor has shown promise as a potential pathogen-agnostic immunomodulator in a variety of preclinical animal models. Additionally, investigator-led studies demonstrated plerixafor prevents viral and bacterial infections in patients with WHIM syndrome, a rare immunodeficiency with aberrant CXCR4 signaling. Here, we investigated whether plerixafor could be repurposed to treat sepsis or severe wound infections, either alone or as an adjunct therapy. In a Pseudomonas aeruginosa lipopolysaccharide (LPS)-induced zebrafish sepsis model, plerixafor reduced sepsis mortality and morbidity assessed by tail edema. There was a U-shaped response curve with the greatest effect seen at 0.1 µM concentration. We used Acinetobacter baumannii infection in a neutropenic murine thigh infection model. Plerixafor did not show reduced bacterial growth at 24 h in the mouse thigh model, nor did it amplify the effects of a rifampin antibiotic therapy, in varying regimens. While plerixafor did not mitigate or treat bacterial wound infections in mice, it did reduce sepsis mortality in zebra fish. The observed mortality reduction in our LPS model of zebrafish was consistent with prior research demonstrating a mortality benefit in a murine model of sepsis. However, based on our results, plerixafor is unlikely to be successful as an adjunct therapy for wound infections. Further research is needed to better define the scope of plerixafor as a pathogen-agnostic therapy. Future directions may include the use of longer acting CXCR4 antagonists, biased CXCR4 signaling, and optimization of animal models.
Subject(s)
Benzylamines , Cyclams , Disease Models, Animal , Heterocyclic Compounds , Receptors, CXCR4 , Sepsis , Zebrafish , Animals , Cyclams/pharmacology , Cyclams/administration & dosage , Benzylamines/pharmacology , Sepsis/drug therapy , Sepsis/microbiology , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/administration & dosage , Mice , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/metabolism , Thigh/microbiology , Acinetobacter Infections/drug therapy , Acinetobacter Infections/microbiology , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/isolation & purification , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Female , Lipopolysaccharides , Wound Infection/microbiology , Wound Infection/drug therapy , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic useABSTRACT
The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of phospho-RSK levels in HepG2 cells and tumor xenografts.
Subject(s)
Drug Discovery , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Cell Line, Tumor , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Enzyme Activation/drug effects , Hep G2 Cells , Humans , Inhibitory Concentration 50 , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyridines/chemistry , Pyrimidines/chemistry , Small Molecule Libraries , Structure-Activity RelationshipABSTRACT
Transketolase, a key enzyme in the pentose phosphate pathway, has been suggested as a target for inhibition in the treatment of cancer. Compound 5a ('N3'-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of the transketolase cofactor thiamine, is a potent transketolase inhibitor but suffers from poor pharmacokinetics due to high clearance and C(max) linked toxicity. An efficient way of improving the pharmacokinetic profile of 5a is to prepare oxidized prodrugs which are slowly reduced in vivo yielding longer, sustained blood levels of the drug. The synthesis of such prodrugs and their evaluation in rodent models is reported.
