RESUMO
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.
Assuntos
Descoberta de Drogas , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Combinatória , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Células Hep G2 , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Pirimidinas/química , Bibliotecas de Moléculas Pequenas , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Benzilaminas , Ciclamos , Modelos Animais de Doenças , Compostos Heterocíclicos , Receptores CXCR4 , Sepse , Peixe-Zebra , Animais , Ciclamos/farmacologia , Ciclamos/administração & dosagem , Benzilaminas/farmacologia , Sepse/tratamento farmacológico , Sepse/microbiologia , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/administração & dosagem , Camundongos , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/metabolismo , Coxa da Perna/microbiologia , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/isolamento & purificação , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Feminino , Lipopolissacarídeos , Infecção dos Ferimentos/microbiologia , Infecção dos Ferimentos/tratamento farmacológico , Antibacterianos/farmacologia , Antibacterianos/uso terapêuticoRESUMO
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.