RESUMEN
In this article we describe the identification of unprecedented ATP-competitive ChoKα inhibitors starting from initial hit NMS-P830 that binds to ChoKα in an ATP concentration-dependent manner. This result is confirmed by the co-crystal structure of NMS-P830 in complex with Δ75-ChoKα. NMS-P830 is able to inhibit ChoKα in cells resulting in the reduction of intracellular phosphocholine formation. A structure-based medicinal chemistry program resulted in the identification of selective compounds that have good biochemical activity, solubility and metabolic stability and are suitable for further optimization. The ChoKα inhibitors disclosed in this article demonstrate for the first time the possibility to inhibit ChoKα with ATP-competitive compounds.
Asunto(s)
Adenosina Trifosfato/antagonistas & inhibidores , Colina Quinasa/antagonistas & inhibidores , Ciclohexanos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Adenosina Trifosfato/metabolismo , Colina Quinasa/metabolismo , Ciclohexanos/síntesis química , Ciclohexanos/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
Compound 1, a hit from the screening of our chemical collection displaying activity against JAK2, was deconstructed for SAR analysis into three regions, which were explored. A series of compounds was synthesized leading to the identification of the potent and orally bioavailable JAK2 inhibitor 16 (NMS-P830), which showed an encouraging tumour growth inhibition in SET-2 xenograft tumour model, with evidence for JAK2 pathway suppression demonstrated by in vivo pharmacodynamic effects.
Asunto(s)
Amidas/síntesis química , Antineoplásicos/síntesis química , Janus Quinasa 2/antagonistas & inhibidores , Leucemia Megacarioblástica Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/síntesis química , Pirroles/síntesis química , Amidas/farmacología , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Expresión Génica , Ensayos Analíticos de Alto Rendimiento , Humanos , Janus Quinasa 2/química , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Leucemia Megacarioblástica Aguda/enzimología , Leucemia Megacarioblástica Aguda/genética , Leucemia Megacarioblástica Aguda/patología , Células Progenitoras de Megacariocitos/efectos de los fármacos , Células Progenitoras de Megacariocitos/enzimología , Células Progenitoras de Megacariocitos/patología , Ratones , Ratones Desnudos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.