RESUMO
Lactate dehydrogenase-A (LDHA) is the major isoform of lactate dehydrogenases (LDH) that is overexpressed and linked to poor survival in pancreatic ductal adenocarcinoma (PDAC). Despite some progress, current LDH inhibitors have poor structural and physicochemical properties or exhibit unfavorable pharmacokinetics that have hampered their development. The present study reports the synthesis and biological evaluation of a novel class of LDHA inhibitors comprising a succinic acid monoamide motif. Compounds 6 and 21 are structurally related analogs that demonstrated potent inhibition of LDHA with IC50s of 46 nM and 72 nM, respectively. We solved cocrystal structures of compound 21-bound to LDHA that showed that the compound binds to a distinct allosteric site between the two subunits of the LDHA tetramer. Inhibition of LDHA correlated with reduced lactate production and reduction of glycolysis in MIA PaCa-2 pancreatic cancer cells. The lead compounds inhibit the proliferation of human pancreatic cancer cell lines and patient-derived 3D organoids and exhibit a synergistic cytotoxic effect with the OXPHOS inhibitor phenformin. Unlike current LDHA inhibitors, 6 and 21 have appropriate pharmacokinetics and ligand efficiency metrics, exhibit up to 73% oral bioavailability, and a cumulative half-life greater than 4 h in mice.
Assuntos
Antineoplásicos , Proliferação de Células , Inibidores Enzimáticos , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Animais , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Proliferação de Células/efeitos dos fármacos , Administração Oral , Camundongos , Relação Estrutura-Atividade , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , L-Lactato Desidrogenase/antagonistas & inibidores , L-Lactato Desidrogenase/metabolismo , Linhagem Celular Tumoral , Modelos MolecularesRESUMO
OBJECTIVE: To develop a quality improvement initiative to reduce the incidence of pulmonary embolism (PE) following elective lower extremity joint replacement surgery. METHODS: 866 Patients undergoing a total knee or total or partial hip replacement surgery at a from 2014 to 2016 were included in this prospective pre-post interventional study. RESULTS: There were 13 PE's before the intervention and 2 after the intervention. The incidence of PE was significantly higher prior to the intervention (2.8% vs. 0.7%; pâ¯=â¯0.044). CONCLUSIONS: Our results suggest that our bundle of interventions was successfully implemented and helped to reduce the incidence of pulmonary embolism following surgery.