RESUMEN
Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inactivator of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes, suggesting this may be used as a predictive biomarker of activity.
Asunto(s)
Antineoplásicos/administración & dosificación , Benzoatos/administración & dosificación , Ciclopropanos/administración & dosificación , Metilación de ADN/efectos de los fármacos , Inhibidores Enzimáticos/administración & dosificación , Histona Demetilasas/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Administración Oral , Animales , Antineoplásicos/farmacología , Benzoatos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclopropanos/farmacología , Inhibidores Enzimáticos/farmacología , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Demetilasas/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Datos de Secuencia Molecular , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A pyrrolopyridinyl thiophene carboxamide 7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of 7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3beta.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Piridinas/síntesis química , Piridinas/farmacología , Tiofenos/química , Animales , Cristalografía por Rayos X , Descubrimiento de Drogas/métodos , Humanos , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Tienopiridinas , Tiofenos/síntesis química , Tiofenos/farmacologíaRESUMEN
AKT inhibitors containing an imidazopyridine aminofurazan scaffold have been optimized. We have previously disclosed identification of the AKT inhibitor GSK690693, which has been evaluated in clinical trials in cancer patients. Herein we describe recent efforts focusing on investigating a distinct region of this scaffold that have afforded compounds (30 and 32) with comparable activity profiles to that of GSK690693.
