RESUMEN
PTC596 is an investigational small-molecule tubulin-binding agent. Unlike other tubulin-binding agents, PTC596 is orally bioavailable and is not a P-glycoprotein substrate. So as to characterize PTC596 to position the molecule for optimal clinical development, the interactions of PTC596 with tubulin using crystallography, its spectrum of preclinical in vitro anticancer activity, and its pharmacokinetic-pharmacodynamic relationship were investigated for efficacy in multiple preclinical mouse models of leiomyosarcomas and glioblastoma. Using X-ray crystallography, it was determined that PTC596 binds to the colchicine site of tubulin with unique key interactions. PTC596 exhibited broad-spectrum anticancer activity. PTC596 showed efficacy as monotherapy and additive or synergistic efficacy in combinations in mouse models of leiomyosarcomas and glioblastoma. PTC596 demonstrated efficacy in an orthotopic model of glioblastoma under conditions where temozolomide was inactive. In a first-in-human phase I clinical trial in patients with cancer, PTC596 monotherapy drug exposures were compared with those predicted to be efficacious based on mouse models. PTC596 is currently being tested in combination with dacarbazine in a clinical trial in adults with leiomyosarcoma and in combination with radiation in a clinical trial in children with diffuse intrinsic pontine glioma.
Asunto(s)
Bencimidazoles/farmacología , Glioblastoma/tratamiento farmacológico , Leiomiosarcoma/tratamiento farmacológico , Pirazinas/farmacología , Moduladores de Tubulina/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Apoptosis , Bencimidazoles/farmacocinética , Proliferación Celular , Femenino , Glioblastoma/patología , Humanos , Leiomiosarcoma/patología , Masculino , Dosis Máxima Tolerada , Ratones , Ratones Desnudos , Persona de Mediana Edad , Pronóstico , Pirazinas/farmacocinética , Distribución Tisular , Moduladores de Tubulina/farmacocinética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-COV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS-COV-2 replication (EC50 range, 2.0-31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17 F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.
Asunto(s)
Antivirales/farmacología , Carbamatos/farmacología , Carbazoles/farmacología , Citocinas/antagonistas & inhibidores , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , SARS-CoV-2/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Animales , Chlorocebus aethiops , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Citocinas/inmunología , Dihidroorotato Deshidrogenasa , Células HeLa , Humanos , Inflamación/tratamiento farmacológico , Inflamación/virología , Células Vero , Tratamiento Farmacológico de COVID-19RESUMEN
The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-CoV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally available compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS CoV-2 replication (EC 50 range, 2.0 to 31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.
RESUMEN
The prevailing paradigm is that T cell differentiation is dependent on interactions between stem cells and neuroectodermal thymic cells in the context of a three-dimensional environment. We evaluated the utility of a three-dimensional matrix, the Cytomatrix, to facilitate T cell differentiation. Thymus stroma grown on the Cytomatrix and seeded with hematopoietic progenitors was observed to support the development of both CD4(+) and CD8(+) T cells. Murine transgenic models used to address T cell selection demonstrated that both positive and negative selection was maintained in the context of MHC Class I. These data demonstrate that this in vitro system using neuroectoderm tissue is capable of the efficient production of T cells from hematopoietic progenitors and presents the possibility of generating and adoptively transferring immune cells to patients.