RESUMEN
Prolyl hydroxylases (PHDs) down-regulate the level of hypoxia-inducible factors (HIFs) by hydroxylating key proline residues that trigger the degradation of the protein and affect the cell and its ability to respond to hypoxic stress. Several small molecule PHD inhibitors are now in various preclinical and clinical stages for the treatment of anemia. The present study provides a detail kinetic analysis for some of these inhibitors. The data generated in the present study suggest that these compounds are reversible and compete directly with the co-substrate, 2-oxoglutarate (2-OG) for binding at the enzyme active site. Most of these compounds are pan PHD inhibitors and exhibit a time-dependent inhibition (TDI) mechanism due to an extremely slow dissociation rate constant, koff, and a long residence time.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Dominio Catalítico , Inhibidores Enzimáticos/química , Humanos , Prolina Dioxigenasas del Factor Inducible por Hipoxia/química , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Ácidos Cetoglutáricos/metabolismo , Cinética , Unión Proteica , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Diseño de Fármacos , Imidazoles/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pteridinas/síntesis química , Animales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Células HT29 , Xenoinjertos , Humanos , Imidazoles/química , Imidazoles/farmacología , Ratones , Estructura Molecular , Pteridinas/química , Pteridinas/farmacología , Relación Estructura-Actividad , Quinasa Tipo Polo 1RESUMEN
Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate. Iterative optimization of the initial lead compound (1) led to compound (21), a selective and potent inhibitor of wild-type Axl. Compound (21) will serve as a useful compound for further in vivo studies.
Asunto(s)
Imidazoles/química , Imidazoles/farmacología , Mutación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genética , Cristalografía por Rayos X , Estructura Molecular , Tirosina Quinasa c-Mer , Tirosina Quinasa del Receptor AxlRESUMEN
Structure based drug design of a series of novel 1,4-benzoxazin-3-one derived PARP-1 inhibitors are described. The synthesis, enzymatic & cellular activities and pharmacodynamic effects are described. Optimized analogs demonstrated inhibition of poly-ADP-ribosylation in SW620 tumor bearing nude mice through 24h following a single dose.
Asunto(s)
Benzoxazinas/química , Benzoxazinas/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Línea Celular Tumoral , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Ratones , Ratones Desnudos , Estructura MolecularRESUMEN
Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies.
Asunto(s)
Azepinas/química , Azepinas/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Ácido 4-Aminobenzoico/química , Ácido 4-Aminobenzoico/farmacocinética , Ácido 4-Aminobenzoico/farmacología , Administración Oral , Adulto , Azepinas/farmacocinética , Línea Celular Tumoral , Descubrimiento de Drogas , Humanos , Inhibidores de Proteínas Quinasas/farmacocinética , Adulto Joven , Quinasa Tipo Polo 1RESUMEN
A highly convergent total synthesis of the potent anticancer agent (+)-phorboxazole A (1) is accomplished. Four components (3-6) are assembled with considerations for control of absolute and relative stereochemistry. Iterative asymmetric allylation methodology addresses key stereochemical features in the preparation of the 2,6-cis- and 2,6-trans-tetrahydropyranyl rings of the C3-C19 component (3). The stereocontrolled asymmetric allylation process is also used for development of the C28-C41 fragment (4). Novel Barbier coupling reactions of alpha-iodomethyl oxazoles and related thiazoles are described with samarium iodide. The convergent assembly of components 4 and 5 features formation of the fully substituted C22-C26 pyran by intramolecular capture of an allyl cation intermediate with high facial selectivity, and further efforts lead to E-C19/C20 olefination. The synthesis culminates with use of a modified Julia olefination for attachment of the C42-C46 segment and subsequent late-stage macrocyclization by installation of the (Z)-C2/C3 alpha,beta-unsaturated lactone.