RESUMO
A series of novel diaryl ether lactams have been identified as very potent dual inhibitors of protein farnesyltransferase (FTase) and protein geranylgeranyltransferase I (GGTase-I), enzymes involved in the prenylation of Ras. The structure of the complex formed between one of these compounds and FTase has been determined by X-ray crystallography. These compounds are the first reported to inhibit the prenylation of the important oncogene Ki-Ras4B in vivo. Unfortunately, doses sufficient to achieve this endpoint were rapidly lethal.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas de Transporte/metabolismo , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP40 , Proteínas de Choque Térmico/metabolismo , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Prenilação de Proteína , Relação Estrutura-Atividade , Transplante Heterólogo , Células Tumorais Cultivadas , Proteínas rap1 de Ligação ao GTP/metabolismo , Proteínas ras/metabolismoRESUMO
A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Hidrocarboneto de Aril Hidroxilases , Proteínas de Transporte de Cátions , Proteínas de Ligação a DNA , Inibidores Enzimáticos/síntese química , Naftalenos/síntese química , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Pirrolidinas/síntese química , Transativadores , Animais , Linhagem Celular , Cromatografia Líquida , Cristalografia por Raios X , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Cães , Canal de Potássio ERG1 , Eletrocardiografia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Canais de Potássio Éter-A-Go-Go , Farnesiltranstransferase , Humanos , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Estrutura Molecular , Naftalenos/química , Naftalenos/farmacocinética , Oxirredutases N-Desmetilantes/antagonistas & inibidores , Canais de Potássio/metabolismo , Ligação Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Estereoisomerismo , Relação Estrutura-Atividade , Regulador Transcricional ERGRESUMO
Compound 1 has been shown to be a dual prenylation inhibitor with FPTase (IC50=2 nM) and GGPTase-I (IC50=95 nM). Analogues of 1, which replaced the cyanophenyl group with various biaryls, led to the discovery of highly potent dual FPTase/GGPTase-I inhibitors. 4-trifluoromethylphenyl, trifluoropentynyl, and trifluoropentyl were identified as good p-cyano replacements.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/químicaRESUMO
A series of macrocyclic piperazinone compounds with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity was prepared. These compounds were found to be potent inhibitors of protein prenylation in cell culture. A hypothesis for the binding mode of compound 3o in FPTase is proposed.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/farmacologia , Piperazinas/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Inibidores Enzimáticos/química , Compostos Heterocíclicos/química , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piperazinas/química , Prenilação de Proteína , Relação Estrutura-Atividade , Células Tumorais Cultivadas/enzimologiaRESUMO
We have prepared a series of potent, dual inhibitors of the prenyl transferases farnesyl protein transferase (FPTase) and geranyl-geranyl protein transferase I (GGPTase). The compounds were shown to possess potent activity against both enzymes in cell culture. Mechanistic analysis has shown that the compounds are CAAX competitive for FPTase inhibition but geranyl-geranyl pyrophosphate (GGPP) competitive for GGPTase inhibiton.