Sudhan Debnath1, Manupati Kanakaraju2, Minarul Islam1, Ragini Yeeravalli2, Debanjan Sen3, Amitava Das4. 1. Department of Chemistry, Maharaja Bir Bikram College, Agartala, 799 004, Tripura, India. 2. Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500 007, India; Academy of Scientific & Innovative Research, 2 Rafi Marg, New Delhi, 110 001, India. 3. Department of Pharmacy, BCDA College of Pharmacy and Technology, Hridaypur, Kolkata, 700 127, India. 4. Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500 007, India; Academy of Scientific & Innovative Research, 2 Rafi Marg, New Delhi, 110 001, India. Electronic address: amitavadas@iict.res.in.
Abstract
BACKGROUND & OBJECTIVE: Epidermal growth factor receptor (EGFR) signaling pathway is one of the promising and well-established targets for anticancer therapy. The objective of the present study was to identify new EGFR inhibitors using ligand and structure-based drug designing methods, followed by a synthesis of selected inhibitors and evaluation of their activity. METHODS: A series of C-7-hydroxyproton substituted chrysin derivatives were virtually drawn to generate a small compound library that was screened using 3D QSAR model created from forty-two known EGFR tyrosine kinase inhibitors. Next, the obtained hits with fitness score ≥ 1.0 were subjected to molecular docking analysis. Based on the predicted activity and XP glide score, three EGFR inhibitors were synthesized and characterized using 1H-NMR, 13C-NMR and MS. Finally, comparative in vitro investigation of the biological activity of synthesized inhibitors was performed with that of the parent molecule, chrysin. RESULTS: The data depicted a 3.2-fold enhanced cytotoxicity of chrysin derivative, CHM-04 against breast cancer cells as compared with chrysin as well as its binding with EGFR protein. Furthermore, the biological activity of CHM-04 was comparable to the standard EGFR inhibitor, AG1478 in increasing apoptosis and decreasing the migratory potential of triple-negative breast cancer cells as well as significantly lowering the mammosphere forming ability of breast cancer stem cells. CONCLUSION: The present study suggests CHM-04, an EGFR inhibitor possessing drug-like properties as a plausible therapeutic candidate against breast cancer.
BACKGROUND & OBJECTIVE:Epidermal growth factor receptor (EGFR) signaling pathway is one of the promising and well-established targets for anticancer therapy. The objective of the present study was to identify new EGFR inhibitors using ligand and structure-based drug designing methods, followed by a synthesis of selected inhibitors and evaluation of their activity. METHODS: A series of C-7-hydroxyproton substituted chrysin derivatives were virtually drawn to generate a small compound library that was screened using 3D QSAR model created from forty-two known EGFR tyrosine kinase inhibitors. Next, the obtained hits with fitness score ≥ 1.0 were subjected to molecular docking analysis. Based on the predicted activity and XP glide score, three EGFR inhibitors were synthesized and characterized using 1H-NMR, 13C-NMR and MS. Finally, comparative in vitro investigation of the biological activity of synthesized inhibitors was performed with that of the parent molecule, chrysin. RESULTS: The data depicted a 3.2-fold enhanced cytotoxicity of chrysin derivative, CHM-04 against breast cancer cells as compared with chrysin as well as its binding with EGFR protein. Furthermore, the biological activity of CHM-04 was comparable to the standard EGFR inhibitor, AG1478 in increasing apoptosis and decreasing the migratory potential of triple-negative breast cancer cells as well as significantly lowering the mammosphere forming ability of breast cancer stem cells. CONCLUSION: The present study suggests CHM-04, an EGFR inhibitor possessing drug-like properties as a plausible therapeutic candidate against breast cancer.
Authors: Marjan Talebi; Mohsen Talebi; Tahereh Farkhondeh; Jesus Simal-Gandara; Dalia M Kopustinskiene; Jurga Bernatoniene; Saeed Samarghandian Journal: Cancer Cell Int Date: 2021-04-15 Impact factor: 5.722