Small molecule 6''-O-Malonylglycitin inhibits ERK2 activity and promotes cytotoxicity in colon adenocarcinoma cells paving for the colon cancer treatment

Amany I. Alqosaibi

Abstract


Background: Extracellular signal-regulated kinase 2 (ERK2), an important component of the MAPK signalling pathway, plays an critical role in the proliferation & survival of colon adenocarcinoma cells. Inhibition of ERK2 can interrupt these oncogenic pathways, offering a capable therapeutic strategy. Natural product-derived small molecules offer substantial potential in this context due to their favourable bioavailability & typically low toxicity.

Methods: This study examines the inhibitory effects of 6''-O-Malonylglycitin on ERK2 kinase activity & its cytotoxic effects on HCT-15 colon adenocarcinoma cells. The crystal structure of ERK2 (PDB ID: 2OJJ) was prepared for molecular docking studies, and 188 isoflavone natural compounds were screened using AutoDock Vina. Among these, 6''-O-Malonylglycitin exhibited the highest binding affinity (-9.3 kcal/mol) with ERK2, forming multiple hydrogen bonds & van der Waals interactions.

Results: The compound was evaluated for cytotoxicity by using an MTT assay, showing a dose-dependent reduction in cell viability with an IC50 of 15.33 µM. Time-dependent studies presented demonstrated significant decreases in cell viability up to 48 hours. Quantitative PCR indicated a significant reduction in ERK2 mRNA expression following treatment with 6''-O-Malonylglycitin. Kinase inhibition assay confirmed a concentration-dependent decrease in ERK2 activity.

Conclusion: The findings indicate that 6''-O-malonylglycitin effectively inhibits ERK2 kinase activity and exhibits potent cytotoxic effects against HCT-15 colon adenocarcinoma cells, suggesting its potential as a therapeutic agent for colon cancer.

Key words: Colon adenocarcinoma; ERK2; HCT-15 cells; small molecule inhibitors; 6''-O-Malonylglycitin


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DOI: http://dx.doi.org/10.62940/als.v12i4.3765

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