RESUMEN
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.
Asunto(s)
Encéfalo , Diseño de Fármacos , Inhibidores Enzimáticos , Metionina Adenosiltransferasa , Metionina Adenosiltransferasa/antagonistas & inhibidores , Metionina Adenosiltransferasa/metabolismo , Humanos , Animales , Relación Estructura-Actividad , Ratas , Encéfalo/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/síntesis química , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/síntesis química , Ratones , Masculino , Ratas Sprague-Dawley , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A new substitution pattern of BF2 azadipyrromethene (azaBODIPY) dyes was obtained by phenanthrene fusion through a key palladium-catalyzed intramolecular C-H activation reaction. These [a]-phenanthrene-fused azaBODIPYs have a near planar structure of the phenanthrene-fused azadipyrromethene core in the crystalline state. The chromophore absorbs (log ε > 5) and fluoresces (Ï = 0.32-0.38) strongly above 700 nm with excellent photostability and may be used as an attractive bright NIR bioimaging agent.
RESUMEN
A new class of phenanthrene-fused BF2 azadipyrromethene (azaBODIPY) dyes have been synthesized through a tandem Suzuki reaction and oxidative ring-fusion reaction, or a palladium-catalyzed intramolecular C-H activation reaction. These phenanthrene-fused azaBODIPY dyes are highly photostable and display markedly redshifted absorption (up to λ=771â nm) and emission bands (λ≈800â nm) in the near-infrared region. DFT calculations and cyclic voltammetry studies indicate that, upon annulation, more pronounced stabilization of the LUMO is the origin of the bathochromic shift of the absorption and high photostability.