Molecules (Aug 2022)

In Vivo Anticancer Evaluation of 6b, a Non-Covalent Imidazo[1,2-<i>a</i>]quinoxaline-Based Epidermal Growth Factor Receptor Inhibitor against Human Xenograft Tumor in Nude Mice

  • Zahid Rafiq Bhat,
  • Manvendra Kumar,
  • Nisha Sharma,
  • Umesh Prasad Yadav,
  • Tashvinder Singh,
  • Gaurav Joshi,
  • Brahmam Pujala,
  • Mohd Raja,
  • Joydeep Chatterjee,
  • Kulbhushan Tikoo,
  • Sandeep Singh,
  • Raj Kumar

DOI
https://doi.org/10.3390/molecules27175540
Journal volume & issue
Vol. 27, no. 17
p. 5540

Abstract

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Tyrosine kinase inhibitors are validated therapeutic agents against EGFR-mutated non-small cell lung cancer (NSCLC). However, the associated critical side effects of these agents are inevitable, demanding more specific and efficient targeting agents. Recently, we have developed and reported a non-covalent imidazo[1,2-a]quinoxaline-based EGFR inhibitor (6b), which showed promising inhibitory activity against the gefitinib-resistant H1975(L858R/T790M) lung cancer cell line. In the present study, we further explored the 6b compound in vivo by employing the A549-induced xenograft model in nude mice. The results indicate that the administration of the 6b compound significantly abolished the growth of the tumor in the A549 xenograft nude mice. Whereas the control mice bearing tumors displayed a declining trend in the survival curve, treatment with the 6b compound improved the survival profile of mice. Moreover, the histological examination showed the cancer cell cytotoxicity of the 6b compound was characterized by cytoplasmic destruction observed in the stained section of the tumor tissues of treated mice. The immunoblotting and qPCR results further signified that 6b inhibited EGFR in tissue samples and consequently altered the downstream pathways mediated by EGFR, leading to a reduction in cancer growth. Therefore, the in vivo findings were in corroboration with the in vitro results, suggesting that 6b possessed potential anticancer activity against EGFR-dependent lung cancer. 6b also exhibited good stability in human and mouse liver microsomes.

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