RESUMO
KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inhibitors to bind KRASG12D with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRASG12D inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model.
Assuntos
Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Animais , Antineoplásicos/química , Descoberta de Drogas , Humanos , Camundongos , Modelos Moleculares , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The first report of the antiviral activity of (+)-sattabacin against varicella-zoster virus (VZV) is described. Our results show that (+)-sattabacin potently inhibits the growth of VZV at concentrations in the range of other drugs commonly prescribed for VZV infection. Experiments detailing the synthesis of (+)-sattabacin, quantification of cytotoxicity and gene expression data in human fibroblast cells are also presented. Gene expression data was obtained through microarray analysis from human fibroblast cells exposed to sattabacin in order to identify a possible mechanism by which (+)-sattabacin inhibits VZV replication.
