RESUMEN
Acute myeloid leukemia (AML) remains a serious unmet medical need. Despite high remission rates with chemotherapy standard-of-care treatment, the disease eventually relapses in a major proportion of patients. Activating Fms-like tyrosine kinase 3 (FLT3) mutations are found in approximately 30% of patients with AML. Targeting FLT3 receptor tyrosine kinase has shown encouraging results in treating FLT3-mutated AML. Responses, however, are not sustained and acquired resistance has been a clinical challenge. Treatment options to overcome resistance are currently the focus of research. We report here the preclinical evaluation of AMG 925, a potent, selective, and bioavailable FLT3/cyclin-dependent kinase 4 (CDK4) dual kinase inhibitor. AMG 925 inhibited AML xenograft tumor growth by 96% to 99% without significant body weight loss. The antitumor activity of AMG 925 correlated with the inhibition of STAT5 and RB phosphorylation, the pharmacodynamic markers for inhibition of FLT3 and CDK4, respectively. In addition, AMG 925 was also found to inhibit FLT3 mutants (e.g., D835Y) that are resistant to the current FLT3 inhibitors (e.g., AC220 and sorafenib). CDK4 is a cyclin D-dependent kinase that plays an essential central role in regulating cell proliferation in response to external growth signals. A critical role of the CDK4-RB pathway in cancer development has been well established. CDK4-specific inhibitors are being developed for treating RB-positive cancer. AMG 925, which combines inhibition of two kinases essential for proliferation and survival of FLT3-mutated AML cells, may improve and prolong clinical responses.
Asunto(s)
Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Naftiridinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ratones , Ratones Desnudos , Naftiridinas/farmacocinética , Naftiridinas/uso terapéutico , Neoplasias Experimentales , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos de Fenilurea/farmacología , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacocinética , Piridinas/farmacología , Transducción de Señal/efectos de los fármacos , Sorafenib , Células U937 , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kß/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kß and δ isoforms in the treatment of a number of inflammatory diseases.