RESUMO
Preclinical and emerging clinical evidence suggests that inhibiting insulin-like growth factor 1 receptor (IGF-1R) signaling may offer a promising therapeutic strategy for the treatment of several types of cancer. This Letter describes the medicinal chemistry effort towards a series of 8-amino-imidazo[1,5-a]pyrazine derived inhibitors of IGF-1R which features a substituted quinoline moiety at the C1 position and a cyclohexyl linking moiety at the C3 position. Lead optimization efforts which included the optimization of structure-activity relationships and drug metabolism and pharmacokinetic properties led to the identification of compound 9m, a potent, selective and orally bioavailable inhibitor of IGF-1R with in vivo efficacy in an IGF-driven mouse xenograft model.
Assuntos
Antineoplásicos/química , Benzimidazóis/química , Imidazóis/química , Inibidores de Proteínas Quinases/química , Pirazinas/química , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Benzimidazóis/farmacocinética , Benzimidazóis/uso terapêutico , Camundongos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/farmacocinética , Pirazinas/uso terapêutico , Receptor IGF Tipo 1/metabolismo , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
A series of novel, potent quinolinyl-derived imidazo[1,5-a]pyrazine IGF-IR (IGF-1R) inhibitors--most notably, cis-3-(3-azetidin-1-ylmethylcyclobutyl)-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine (AQIP)--is described. Synthetic details, structure-activity relationships, and in vitro biological activity are reported for the series. Key in vitro and in vivo biological results for AQIP are reported, including: inhibition of ligand-stimulated autophosphorylation of IGF-IR and downstream pathways in 3T3/huIGFIR cells; inhibition of proliferation and induction of DNA fragmentation in human tumor cell lines; a pharmacokinetic profile suitable for once-per-day oral dosing; antitumor activity in a 3T3/huIGFIR xenograft model; and effects on insulin and glucose levels.
Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Quinolinas/química , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Glicemia/metabolismo , Linhagem Celular , Cães , Feminino , Humanos , Imidazóis/química , Insulina/sangue , Ligantes , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Pirazinas/química , Ratos , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Insulin-like growth factor-I receptor (IGF-IR) and its ligands, IGF-I and IGF-II, are up-regulated in a variety of human cancers. In tumors, such as colorectal, non-small cell lung, ovarian, and pediatric cancers, which may drive their own growth and survival through autocrine IGF-II expression, the role of IGF-IR is especially critical. Here, we present a novel small-molecule IGF-IR kinase inhibitor, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP), which displayed a cellular IC(50) of 19 nmol/L for inhibition of ligand-dependent autophosphorylation of human IGF-IR with 14-fold cellular selectivity relative to the human insulin receptor. PQIP showed minimal activity against a panel of 32 other protein kinases. It also abolished the ligand-induced activation of downstream phosphorylated AKT and phosphorylated extracellular signal-regulated kinase 1/2 in both IGF-IR transfectant cells and a GEO human colorectal cancer cell line. Analysis of GEO cells revealed a significant level of both phosphorylated IGF-IR and IGF-II expression. Furthermore, inactivation of IGF-II in conditioned GEO culture medium by a neutralizing antibody diminished IGF-IR activation, indicating the presence of a functional IGF-II/IGF-IR autocrine loop in GEO cells. Once daily oral dosing of PQIP induced robust antitumor efficacy in GEO xenografts. The antitumor efficacy correlated with the degree and duration of inhibition of tumor IGF-IR phosphorylation in vivo by this compound. Moreover, when mice were treated for 3 days with a dose of PQIP that maximally inhibited tumor growth, only minor changes in blood glucose were observed. Thus, PQIP represents a potent and selective IGF-IR kinase inhibitor that is especially efficacious in an IGF-II-driven human tumor model.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/patologia , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Comunicação Autócrina/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/química , Imidazóis/farmacocinética , Fator de Crescimento Insulin-Like II/metabolismo , Camundongos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/administração & dosagem , Pirazinas/química , Pirazinas/farmacocinética , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of novel 8-amino-1,3-disubstituted-imidazo[1,5-a]pyrazines was designed and synthesized as IGF-IR inhibitors.