Appraisal and synthesis of novel indole-thiazole derivatives as epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors against resistance mutation for lung cancer treatment

Abstract

For the treatment of NSCLC one of the promising strategies is targeted inhibition of EGFR and its mutants. In this research work, we tend to epitomize design, synthesis, in-vitro anticancer evaluation of novel indole-thiazole derivatives as novel reversible EGFR inhibitor which have trifling toxicity. The structure of the novel indole-thiazole derivatives was designed considering the standard drug EAI045. The detailed study of first generation, second generation, third generation and fourth generation EGFR inhibitors was carried out before the designing of novel indole-thiazole derivatives. The results point toward the novel indole-thiazole derivatives 7(a-n) potential as moderate to excellent anticancer compounds. The SAR studies indicated that compounds 7e, 7f, 7 h, 7 k and 7 l reveals marvellous selective inhibition of EGFRL858R/ T790M over wild type EGFR. Especially, the synthesized compounds 7e (HCC827 IC 50 = 0.23 µM, H1975 IC 50 = 0.38 µM) and 7f (HCC827 IC 50 = 0.34 µM, H1975 IC 50 = 0.42 µM) revealed excellent in vitro anticancer activity and selectivity ratio. The compounds have also shown more selectivity towards cancer cells when compared with normal cell BEAS-2B. This shows that compounds will show minimal toxicity towards normal cells. The enzyme assay results revealed that the compound 7e has an ability to inhibit reversibly EGFR L858R/T790M. The compound 7e possibly appreciably inhibit colony formation and wound healing. The compound 7e was also able to induce apoptosis in cancer cells. The docking study also proofed the aptness to inhibit EGFR L858R/T790M of the synthesized compounds. Our findings suggest that the novel indole-thiazole derivatives 7(a-n), can specifically in vitro and at cellular level, target the mutant EGFRL858R/T790M and will open the new doors for the cancer therapy against EGFR L858R/T790M mutated cancer cells.