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
Myeloid-derived suppressor cells (MDSCs) represent a group of immature myeloid cells composed of myeloid progenitor cells and immature myeloid cells that can negatively regulate immune responses by inhibiting T-cell function. In mice, MDSCs are broadly defined by the expression of CD11b and Gr1. We and others have shown that injection of a lethal or sublethal dose of lipopolysaccharide (LPS) into mice could result in the expansion of MDSCs in the bone marrow (BM), spleen and blood. Until now, the molecular mechanisms responsible for this expansion are poorly studied; specifically, the roles of the individual microRNAs (miRNAs) which may be involved remain largely unknown. We performed microarray analysis to compare the miRNA expression profiles of CD11b+ Gr1+ cells sorted from the BM of LPS-injected and phosphate-buffered saline-injected mice. We identified let-7e, which was highly upregulated in the LPS-treated group, as a potent regulator of LPS-induced MDSC expansion. Furthermore, let-7e overexpression in BM chimeric mice led to a noticeable increase in the population of CD11b+ Gr1+ cells, which resulted from reduced cellular apoptosis. Further studies showed that let-7e could directly target caspase-3 to inhibit cell apoptosis, and upregulation of let-7e in LPS-stimulated MDSCs could be due to the relieved repression of let-7e transcription exerted by downregulated GATA2. Our findings suggest that LPS expands MDSCs by inhibiting apoptosis through the regulation of the GATA2/let-7e axis.