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<p>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 <b>5i</b> 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, <b>5i</b> 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 <b>5i</b> 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 <b>5i</b> has emerged as a promising hit candidate, and can be explored further for development of potent JAK-3 kinase inhibitors targeting breast cancer.</p> Graphical abstract <p></p>

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

  • 期刊论文

  • 发表日期：

    2025年3月3日

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  • Bharti Dhawan,
  • Mohammad Sarwar Alam,
  • Hinna Hamid,
  • Anubha Yadav,
  • Gowsia Akhter,
  • Mohd Jamal Dar,
  • Ozair Alam,
  • Yogisha S

摘要

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.

Graphical abstract