EGFR Inhibitors and Apoptosis Inducers : Design, Docking, Synthesis, and Anticancer Activity of Novel Tri-Chalcone Derivatives

Abstract

Menier Al-Anazi, Melati Khairuddean, Belal O. Al-Najjar, Mohammad Murwih Alidmat, Nik Nur Syazni Nik Mohamed Kamal, Musthahimah Muhamad, Maywan Hariono.

Estrogen receptors (ERs) are primarily expressed in cancer cells and interfere with the epidermal growth factor (EGFR) signal pathway. However, data are limited regarding the interaction between cytoplasmic ER expression and EGFR-tyrosine kinase inhibitor response. The objective of this study was to design multi-target molecules for enhancing anti-cancer activity and decreasing drug resistance. Two distinct series of tri-chalcone derivatives S1(1-7), S2(1-7) with promising anti-cancer activity was incorporated into the current study. Compounds S1(1-2) and S2(1-2) demonstrated the highest binding affinity for interactions with the active EGFR binding site. Interestingly, compounds S1-1 and S1-2 have shown a potent cytotoxicity of MCF-7 (2.23 ± 0.11 and 2.04 ± 0.71 µM) and MDA-MB-231 (6.44 ± 0.01 and 3.75 ± 0.26 µM), respectively, relative to tamoxifen IC50 of 9.3 ± 0.44 and 18.92 ± 1.43 µM. Thus, in-vitro EGFR activity was evaluated for compounds S1-1 and S1-2. The results indicated that compounds S1-1 and S1-2 showed a significant improvement in the anti-cancer resistant treatment due to their potential effects on the EGFR and the possible anti-ER effect.