RESUMEN
Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.
Asunto(s)
Inhibidores Enzimáticos/química , Glutaminasa/antagonistas & inhibidores , Triazoles/farmacocinética , Administración Oral , Animales , Línea Celular Tumoral , Perros , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Glutaminasa/genética , Glutaminasa/metabolismo , Semivida , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Microsomas/metabolismo , Unión Proteica , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Relación Estructura-Actividad , Triazoles/química , Triazoles/metabolismoRESUMEN
Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kß/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kß and δ isoforms in the treatment of a number of inflammatory diseases.
Asunto(s)
Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Modelos MolecularesRESUMEN
The critical issues in docking include the prediction of the correct binding pose and the accurate estimation of the corresponding binding affinity. Different docking methodologies have all been successful in reproducing the crystallographic binding modes but struggle when predicting the corresponding binding affinities. The aim of this work is to evaluate the performance of the MM-GB/SA rescoring of docking poses in structure-based lead optimization. To accomplish that, a diverse set of pharmaceutically relevant targets, including CDK2, FactorXa, Thrombin, and HIV-RT were selected. The correlation between the MM-GB/SA results and experimental data in all cases is remarkable. It even qualifies this approach as a more attractive alternative for rank-ordering than the Free Energy Perturbation and Thermodynamic Integration methodologies because, while as accurate, it can handle more structurally dissimilar ligands and provides results at a fraction of the computational cost. On the technical side, the benefit of performing a conformational analysis and having an ensemble of conformers to represent each ligand in the unbound state during the MM-GB/SA rescoring procedure was investigated. In addition, the estimation of conformational entropy penalties for the ligands upon binding, computed from the Boltzmann distribution in water, was evaluated and compared to a commonly used approach employed by many docking scoring functions.