RESUMEN
The ATR pathway is a critical mediator of the replication stress response in cells. In aberrantly proliferating cancer cells, this pathway can help maintain sufficient genomic integrity for cancer cell progression. Herein we describe the discovery of 19, a pyrazolopyrimidine-containing inhibitor of ATR via a strategic repurposing of compounds targeting PI3K.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Piridinas/química , Pirimidinas/química , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/metabolismo , Piridinas/metabolismo , Pirimidinas/metabolismoRESUMEN
Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice.
Asunto(s)
Amidas/química , Diseño de Fármacos , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Administración Oral , Amidas/síntesis química , Amidas/farmacocinética , Amidas/toxicidad , Animales , Sitios de Unión , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Semivida , Humanos , Concentración 50 Inhibidora , Ratones , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Células RAW 264.7 , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Relación Estructura-ActividadRESUMEN
Melanin concentrating hormone receptor 1 (MCHR1) antagonists have potential for the treatment of obesity and several CNS disorders. In the preceding article, we have described a novel series of quinazolines as MCHR1 antagonists and demonstrated in vivo proof of principle with an early lead. Herein we describe the detailed SAR and SPR studies to identify an optimized lead candidate having good efficacy in a sub-chronic DIO model with a good cardiovascular safety window.