Computational identification and experimental validation of potential inhibitors of JAK1 kinase from natural source for the effective treatment of colorectal adenocarcinoma

Abstract

Colorectal cancer (CRC) has become a global threat worldwide with constantly increasing incidence and mortality rates every year, especially in the US and China. Janus kinase (JAK) is an intracellular non-receptor tyrosine that mediates the signal transducer and activator of transcription (STAT) which orchestrates cytokine signalling, oncogene expression, and modulation of transcription factors. Targeting JAK holds promise as a therapeutic strategy for CRC. This present study focused on natural products, due to their renowned for their diverse pharmacological properties including anticancer, antimicrobial, anti-proliferative, and antioxidant effects. Employing a range of bioinformatics analyses such as molecular docking, drug-likeness evaluation, ADME profiling, toxicity assessment, in silico cytotoxicity prediction, and molecular target identification, and in vitro assays such as cytotoxicity assay & ROS induction assay were performed to investigate the potency of the natural compounds. Among the screened compounds, Methyl betulate (L1), Epigallocatechin-3-gallate (EGCG) (L2), and Eriocalyxin B (L3) exhibited stronger binding affinities than the standard Golidocitinib (AZD4205). These compounds not only met Lipinski's criteria for drug-likeness and displayed favourable ADME properties but also demonstrated reduced toxicity profiles and exhibited promising activity against various kinases. Furthermore, molecular dynamics simulations revealed the stability of these compounds with JAK1. Notably, they also exhibited potent cytotoxicity and induced apoptosis in SW480 and HT29 colon adenocarcinoma cells. Consequently, the findings suggest that these three compounds hold potential as potent JAK1 inhibitors, warranting further investigation in future in vivo studies.