RESUMO
This paper reports a second generation MEK inhibitor. The previously reported potent and efficacious MEK inhibitor, PD-184352 (CI-1040), contains an integral hydroxamate moiety. This compound suffered from less than ideal solubility and metabolic stability. An oxadiazole moiety behaves as a bioisostere for the hydroxamate group, leading to a more metabolically stable and efficacious MEK inhibitor.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Antineoplásicos/química , Benzamidas/química , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/tratamento farmacológico , Técnicas de Química Combinatória , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres , Humanos , Ácidos Hidroxâmicos/química , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Oxidiazóis/química , Relação Estrutura-AtividadeRESUMO
A novel series of benzhydroxamate esters derived from their precursor anthranilic acids have been prepared and have been identified as potent MEK inhibitors. 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide, CI-1040, was the first MEK inhibitor to demonstrate in vivo activity in preclinical animal models and subsequently became the first MEK inhibitor to enter clinical trial. CI-1040 suffered however from poor exposure due to its poor solubility and rapid clearance, and as a result, development of the compound was terminated. Optimization of the diphenylamine core and modification of the hydroxamate side chain for cell potency, solubility, and exposure with oral delivery resulted in the discovery of the clinical candidate N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide PD 0325901.
Assuntos
Benzamidas/síntese química , Difenilamina/análogos & derivados , Inibidores Enzimáticos/síntese química , MAP Quinase Quinase Quinase 1/antagonistas & inibidores , Animais , Benzamidas/farmacologia , Benzoatos/química , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Difenilamina/síntese química , Difenilamina/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Ácidos Hidroxâmicos/química , Concentração Inibidora 50 , Camundongos , Transplante de Neoplasias , Solubilidade , ortoaminobenzoatos/químicaRESUMO
A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate. Most notably, pyridone 27 was found to be more potent than 1 in vitro and produced a 100% response rate at a lower dose than 1, when tested for in vivo efficacy in animals bearing C26 tumors.
Assuntos
Amidas/síntese química , Compostos de Anilina/síntese química , Antineoplásicos/síntese química , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , Piridonas/síntese química , Amidas/química , Amidas/farmacologia , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinase Quinase 1/química , MAP Quinase Quinase 2/química , Masculino , Camundongos , Modelos Moleculares , Transplante de Neoplasias , Fosforilação , Piridonas/química , Piridonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
MEK1 and MEK2 are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. Approximately 30% of all human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here we present the X-ray structures of human MEK1 and MEK2, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 A and 3.2 A, respectively. The structures reveal that MEK1 and MEK2 each have a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitor induces several conformational changes in the unphosphorylated MEK1 and MEK2 enzymes that lock them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition.