RESUMEN
Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-Raf(V600E) mutated enzyme has been observed in a number of human tumors, including melanomas. Herein we report the discovery and biological evaluation of GSK2118436, a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-Raf(V600E) human melanoma. GSK2118436 was identified as a development candidate, and early clinical results have shown significant activity in patients with B-Raf mutant melanoma.
RESUMEN
mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Piridazinas/química , Piridinas/química , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Bencimidazoles/química , Sitios de Unión , Unión Competitiva , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Imidazoles/química , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Terciaria de Proteína , Piridazinas/síntesis química , Piridazinas/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
A class of 2-acyliminobenzimidazoles has been developed as potent and selective inhibitors of anaplastic lymphoma kinase (ALK). Structure based design facilitated the rapid development of structure-activity relationships (SAR) and the optimization of kinase selectivity. Introduction of an optimally placed polar substituent was key to solving issues of metabolic stability and led to the development of potent, selective, orally bioavailable ALK inhibitors. Compound 49 achieved substantial tumor regression in an NPM-ALK driven murine tumor xenograft model when dosed qd. Compounds 36 and 49 show favorable potency and PK characteristics in preclinical species indicative of suitability for further development.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Administración Oral , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Disponibilidad Biológica , Línea Celular Tumoral , Estabilidad de Medicamentos , Humanos , Imidazoles/química , Imidazoles/metabolismo , Imidazoles/farmacocinética , Imidazoles/farmacología , Concentración 50 Inhibidora , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Ratas , Proteínas Tirosina Quinasas Receptoras/química , Proteínas Tirosina Quinasas Receptoras/metabolismo , Especificidad por SustratoRESUMEN
A potent series of inhibitors against the B-Raf(V600E) kinase have been developed that show excellent activity in cellular assays and good oral bioavailability in rats. The key structural features of the series are an arylsulfonamide headgroup, a thiazole core, and a fluorine ortho to the sulfonamide nitrogen.
