2025

Nafie, Mohamed S.; Ali, M.; Alwehaibi, Moayad Abdullah; Alayyaf, Abdulmajeed Abdullah; Al-Muhanna, Muhanna K.; Almuqati, Naif S.; Alghamdi, Abdullah A.; Haukka, Matti; Tariq, Syeda Sumayya; Ul-Haq, Zaheer; Barakat, Assem

The search for effective anti-cancer therapies has led to the exploration of dual inhibition strategies targeting multiple key molecular pathways. In this study, we aimed to design a novel candidate capable of dual inhibition targeting both EGFR (Epidermal Growth Factor Receptor) and PARP-1 (poly(ADP-ribose)polymerase-1), two crucial proteins implicated in cancer progression and resistance mechanisms. Through molecular hybridization and structure-based drug design approaches, we synthesized a series of compounds based on spirooxindole with triazole scaffolds with the potential for dual EGFR and PARP-1 inhibition. Interestingly, compounds 4a, 4b and 4f showed potent cytotoxicity against HepG2 cells with IC50 values of 3.6, 4.6, and 1.9 μM compared to doxorubicin (IC50 = 2.78 μM), with poor cytotoxicity against THLE2 cells with IC50 values higher than 40 μM in a selective way. They exhibited potent EGFR and PARP-1 inhibition with IC50 values of 74.6, 85.3, and 116.1 nM compared to Erlotinib (IC50 = 80 nM, 94.7%). Additionally, they exhibited potent PARP-1 inhibition, with IC50 values of 2.01, 3.6, and 18.4 nM compared to Olaparib (IC50 = 1.49 nM, 94.5%). Furthermore, compound 4a-treatment induced increased apoptosis by 6.6-fold, as the effective cell death mechanism. Overall, our study underscores the importance of multi-targeted approaches in developing effective anti-cancer agents.