RESUMO
Patients with melanoma with activating BRAF mutations (BRAF V600E/K) initially respond to combination therapy of BRAF and MEK inhibitors. However, their clinical efficacy is limited by acquired resistance, in some cases driven by amplification of the mutant BRAF gene and subsequent reactivation of the MAPK pathway. DS03090629 is a novel and orally available MEK inhibitor that inhibits MEK in an ATP-competitive manner. In both in vitro and in vivo settings, potent inhibition of MEK by DS03090629 or its combination with the BRAF inhibitor dabrafenib was demonstrated in a mutant BRAF-overexpressing melanoma cell line model that exhibited a higher MEK phosphorylation level than the parental cell line and then became resistant to dabrafenib and the MEK inhibitor trametinib. DS03090629 also exhibited superior efficacy against a melanoma cell line-expressing mutant MEK1 protein compared with dabrafenib and trametinib. Biophysical analysis revealed that DS03090629 retained its affinity for the MEK protein regardless of its phosphorylation status, whereas the affinity of trametinib declined when the MEK protein was phosphorylated. These results suggest that DS03090629 may be a novel therapeutic option for patients who acquire resistance to the current BRAF- and MEK-targeting therapies.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Melanoma , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf , Humanos , Trifosfato de Adenosina , MAP Quinase Quinase 1/genética , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação , Oximas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
Motilin is a 22-amino-acid gastrointestinal (GI) hormone and is involved in the regulation of GI motility through binding to GPR38, the motilin receptor which is expressed on smooth muscle cells in the GI tract. Therefore, GPR38 agonists are expected to be novel gastrointestinal prokinetic agents for the treatment of functional gastrointestinal disorders such as gastroparesis and chronic constipation. We identified a series of N-methylanilide derivatives as novel non-macrolide GPR38 agonists. Among them, 12 di-l-tartrate (DS-3801b) was selected as a clinical candidate for further evaluation.
Assuntos
Compostos de Anilina/farmacologia , Cicloexanos/farmacologia , Descoberta de Drogas , Fármacos Gastrointestinais/farmacologia , Gastroparesia/tratamento farmacológico , Piperazinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Compostos de Anilina/química , Animais , Cicloexanos/síntese química , Cicloexanos/química , Relação Dose-Resposta a Droga , Fármacos Gastrointestinais/síntese química , Fármacos Gastrointestinais/química , Gastroparesia/metabolismo , Humanos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Coelhos , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
[structure: see text] Synthesis of two diastereomeric models (3a and 3b) corresponding to the CDE/FG ring of prymnesins, polycyclic ether toxins isolated from the red tide phytoflagellate Prymnesium parvum, is described. Comparison of the (1)H and (13)C NMR data for each compound with those reported for prymnesins suggests that the earlier stereochemical assignment of the E/F ring juncture needs to be revised.
