RESUMEN
Inhibitors against the p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias. As p110δ is primarily expressed in leukocytes, drugs against p110δ have not been considered for the treatment of solid tumours. Here we report that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110δ inactivation in regulatory T cells unleashes CD8(+) cytotoxic T cells and induces tumour regression. Thus, p110δ inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Tolerancia Inmunológica/efectos de los fármacos , Neoplasias/enzimología , Neoplasias/inmunología , Fosfatidilinositol 3-Quinasas/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Activación Enzimática/efectos de los fármacos , Tolerancia Inmunológica/inmunología , Ratones , Linfocitos T Reguladores/enzimología , Linfocitos T Reguladores/inmunologíaRESUMEN
A potent inhibitor of PI3Kδ that is ≥ 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Triptófano/química , Animales , Sitios de Unión , Simulación por Computador , Femenino , Inyecciones Intravenosas , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Mutación , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Terciaria de Proteína , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
PI3Kδ is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(α, ß, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδ inhibitors and describe a structural hypothesis for isoform (α, ß, γ) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Inhibidores del Citocromo P-450 CYP3A , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Artritis Reumatoide/enzimología , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Línea Celular , Citocromo P-450 CYP3A , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Fosfatidilinositol 3-Quinasas/química , Conformación Proteica , Especificidad por Sustrato , Factores de TiempoRESUMEN
Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Indazoles/farmacología , Neoplasias/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Sulfonamidas/farmacología , Administración Oral , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Disponibilidad Biológica , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Humanos , Indazoles/administración & dosificación , Indazoles/farmacocinética , Indazoles/uso terapéutico , Espectroscopía de Resonancia Magnética , Estructura Molecular , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéuticoRESUMEN
In our continued effort to identify selective MRP1 modulators, we have developed two novel templates, 3 and 4, through rational drug design by identifying the key pharmacophore interaction at the 7-position of the pyrrolopyrimidine template 1. Further synthesis and SAR work on these novel templates gave a number of potent MRP1 modulators with great selectivity against Pgp. Additional studies to reduce the CYP3A4 inhibition are also reported. Several compounds of these classes were subjected to in vivo xenograft studies and in vivo efficacies were demonstrated.
Asunto(s)
Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirroles/síntesis química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/biosíntesis , Animales , Área Bajo la Curva , Disponibilidad Biológica , Línea Celular Tumoral , Técnicas Químicas Combinatorias , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Doxorrubicina/farmacología , Sinergismo Farmacológico , Femenino , Semivida , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Moleculares , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/biosíntesis , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Pirroles/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The syntheses and SAR studies of various quinazolinone compounds are described for the dual inhibition of Pgp and MRP1 in multidrug resistance.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Resistencia a Múltiples Medicamentos , Quinazolinas/síntesis química , Antibióticos Antineoplásicos/antagonistas & inhibidores , Antibióticos Antineoplásicos/farmacocinética , Antineoplásicos/antagonistas & inhibidores , Antineoplásicos/farmacocinética , Daunorrubicina/antagonistas & inhibidores , Daunorrubicina/farmacocinética , Doxorrubicina/antagonistas & inhibidores , Doxorrubicina/farmacocinética , Interacciones Farmacológicas , Humanos , Concentración 50 Inhibidora , Quinazolinas/química , Quinazolinas/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis and biological activity of this new series of substituted 8,9-benzo[a]phenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein. Selected analogues were evaluated against the COR-L23 parental human non small cell lung carcinoma cell line and the COR-L23/R resistant cell line which overexpresses multidrug resistance protein. This series of novel angular benzophenazines were potent cytotoxic agents in these cell lines and may be able to circumvent multidrug resistance mechanisms which result in the lack of efficacy of many drugs in cancer chemotherapy. These compounds show dual inhibition of topoisomerase I and topoisomerase II and thus target two key enzymes responsible for the topology of DNA that are active at different points in the cell cycle. The introduction of chirality into the carboxamide side chain of these novel benzophenazine carboxamides has resulted in the discovery of a potent enantiospecific series of cytotoxic agents, exemplified by 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576 ((R)-4j' '). In vivo activity has been demonstrated for 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576, after intravenous administration to female mice, and this compound has been selected as a development candidate for further evaluation.