Synthesis and biological evaluation of thiourea-tethered benzodiazepinones as anti-proliferative agents targeting JAK-3 kinase.

Owing to anti-cancer potency of the benzodiazepinone derivatives, the study aims to synthesize a library of thiourea-tethered benzodiazepinone derivatives targeting JAK-3 kinase for anti-breast cancer potency. Test compounds showed favourable in silico interactions with the active site of JAK-3 kinase. Compound 5i demonstrated a significant JAK-3 kinase inhibitory potential of 68.28% and appreciable growth inhibition (72.9%) of MDA-MB-468 (breast cancer cells) as per the anti-proliferative screening done by NCI-USA. In addition, 5i was also found to induce apoptosis moderately by 12.4% in the late apoptosis quadrant and arrested cell cycle at the G2/M phase. The wound healing assay demonstrated the anti-metastatic impact of drug 5i by reducing the migratory potential of MDA-MB-468 cells and was found to be stable within the target protein in the molecular dynamic simulation. All the synthesized compounds exhibited drug-appropriate pharmacokinetic profiles as corroborated by computational ADMET analysis. The study indicates that the synthesized library of benzodiazepinone derivatives is efficacious and compound 5i has emerged as a promising hit candidate, and can be explored further for development of potent JAK-3 kinase inhibitors targeting breast cancer.