RESUMEN
More women die of breast cancer than of any other malignancy. The resistance and toxicity of traditional hormone therapy created an urgent need for potential molecules for treating breast cancer effectively. Novel biphenyl-substituted pyrazole chalcones linked to a pyrrolidine ring were designed by using a hybridization approach. The hybrids were assessed against MCF-7 and MDA-MB-231 cells by NRU assay. Among them, 8 k, 8 d, 8 m, 8 h, and 8 f showed significantly potent IC50 values: 0.17, 5.48, 8.13, 20.51, and 23.61â µM) respectively, on MCF-7 cells compared to the positive control Raloxifene and Tamoxifen. Furthermore, most active compound 8 k [3-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(2-(2-(pyrrolidin-1-yl)-ethoxy)-phenyl)-chalcone] showed cell death induced through apoptosis, cell cycle arrest at the G2/M phase, and demonstrated decrease of ER-α protein in western blotting study. Docking studies of 8 k and 8 d established adequate interactions with estrogen receptor-α as required for SERM binding. The active hybrids exhibited good pharmacokinetic properties for oral bioavailability and drug-likeness. Whereas, RMSD, RMSF, and Rg values from Molecular dynamics studies stipulated stability of the complex formed between compound 8 k and receptor. All of these findings strongly indicate the antiproliferative potential of pyrazole-chalcone hybrids for the treatment of breast cancer.
Asunto(s)
Antineoplásicos , Apoptosis , Neoplasias de la Mama , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Pirazoles , Humanos , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Femenino , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Apoptosis/efectos de los fármacos , Estructura Molecular , Chalconas/química , Chalconas/farmacología , Chalconas/síntesis química , Simulación del Acoplamiento Molecular , Chalcona/química , Chalcona/farmacología , Línea Celular Tumoral , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Animales , RatasRESUMEN
KRASG12C has been identified as a potential target in the treatment of solid tumors. One of the most often transformed proteins in human cancers is the small Kirsten rat sarcoma homolog (KRAS) subunit of GTPase, which is typically the oncogene driver. KRASG12C is altered to keep the protein in an active GTP-binding form. KRAS has long been considered an 'undrugable' target, but sustained research efforts focusing on the KRASG12C mutant cysteine have achieved promising results. For example, the US Food and Drug Administration (FDA) has passed emergency approval for sotorasib and adagrasib for the treatment of metastatic lung cancer. Such achievements have sparked several original approaches to KRASG12C. In this review, we focus on the design, development, and history of KRASG12C inhibitors.