Identification of Vinyl Sulfone Derivatives as EGFR Tyrosine Kinase Inhibitor: In Vitro and In Silico Studies.

Thitinan Aiebchun,Panupong Mahalapbutr,Supaphorn Seetaha,Lueacha Tabtimmai,Kiattawee Choowongkomon,Chutima Kuhakarn,Atima Auepattanapong,Onnicha Khaikate,Thanyada Rungrotmongkol

doi:10.3390/molecules26082211

Abstract

Epidermal growth factor receptor (EGFR), overexpressed in many types of cancer, has been proved as a high potential target for targeted cancer therapy due to its role in regulating proliferation and survival of cancer cells. In the present study, a series of designed vinyl sulfone derivatives was screened against EGFR tyrosine kinase (EGFR-TK) using in silico and in vitro studies. The molecular docking results suggested that, among 78 vinyl sulfones, there were eight compounds that could interact well with the EGFR-TK at the ATP-binding site. Afterwards, these screened compounds were tested for the inhibitory activity towards EGFR-TK using ADP-Glo™ kinase assay, and we found that only VF16 compound exhibited promising inhibitory activity against EGFR-TK with the IC50 value of 7.85 ± 0.88 nM. In addition, VF16 showed a high cytotoxicity with IC50 values of 33.52 ± 2.57, 54.63 ± 0.09, and 30.38 ± 1.37 µM against the A431, A549, and H1975 cancer cell lines, respectively. From 500-ns MD simulation, the structural stability of VF16 in complex with EGFR-TK was quite stable, suggesting that this compound could be a novel small molecule inhibitor targeting EGFR-TK.

Highlights

Cancer is a devastating disease characterized by uncontrolled growth and spread of abnormal cells and is the second leading cause of mortality worldwide [1]
These results suggested that none of the vinyl sulfone derivatives is stronger than erlotinib
The matched van der Waals (vdW) contacts between all Vinyl sulfone (VF) and erlotinib were as follows: (i) hinge region: T766, L768, P770, and G772 and (ii) A loop: K721, E731, T830, and D831. These results suggested that these eight VFs might be the potent candidate compounds acting against epidermal growth factor receptor (EGFR)-tyrosine kinase (TK)

Summary

Introduction

Cancer is a devastating disease characterized by uncontrolled growth and spread of abnormal cells and is the second leading cause of mortality worldwide [1]. The overexpression of epidermal growth factor receptor (EGFR) in cancer cells leads to abnormal signal transduction and is closely related to the occurrence of cancer. It has become one of the most important protein targets for designing and developing kinase inhibitors that act on oncogenic EGFR [6]. Targeting EGFR protein has been suggested as a promising strategy for targeted cancer therapy, since the EGFR is commonly overexpressed in many human cancers, including non-small cell lung, head, breast, bladder and ovarian carcinoma [12,13].

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