RESUMO
Synthetic lethality has recently emerged as a new approach for the treatment of mutated genes that were previously considered undruggable. Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality and thus has attracted significant interest in the field of precise anticancer drug development. Herein, we report the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-c]quinolin-4-one skeleton based on structure-based drug design. Further optimization led to compound 39, which has a high potency for inhibiting MAT2A and a remarkable selectivity for MTAP-deleted cancer cell lines. Compound 39 has a favorable pharmacokinetic profile with high plasma exposure and oral bioavailability, and it exhibits significant efficacy in xenograft MTAP-depleted models. Moreover, 39 demonstrates excellent brain exposure with a Kpuu of 0.64 in rats.
Assuntos
Encéfalo , Desenho de Fármacos , Inibidores Enzimáticos , Metionina Adenosiltransferase , Metionina Adenosiltransferase/antagonistas & inibidores , Metionina Adenosiltransferase/metabolismo , Humanos , Animais , Relação Estrutura-Atividade , Ratos , Encéfalo/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/síntese química , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/síntese química , Camundongos , Masculino , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Several bisacenaphthopyrazinoquinoxaline (BAPQ) based derivatives 1-3 were synthesized by condensation between the acenaphthenequinones and 1,2,4,5-tetraaminobenzene tetrahydrochloride. Their optical, electrochemical and self-assembling properties are tuned by different substituents. Among them, compound 3 possesses a homogeneously distributed low-lying LUMO due to the peripheral substitution with four cyano groups. The corresponding n-channel field effect transistors showed a field effect electron mobility of 5 × 10(-3) cm(2) V(-1) s(-1).
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Quinoxalinas/química , Quinoxalinas/síntese química , Transistores Eletrônicos , Estrutura Molecular , Teoria Quântica , Semicondutores , TemperaturaRESUMO
Linear and star-shaped pyrazinacenes 1a-b and 2 were synthesized via condensation between a new building block 11 and pyrene tetraones or cyclohexaone. Compound 2 represents the largest star-shaped dihydropyrazine fused pyrazinacene reported so far. These largely expanded pyrazinacenes show good solubility and have a strong tendency to aggregate in both solution and thin films, indicating their potential applications for organic electronic devices.