Identification of gefitinib off-targets using a structure-based systems biology approach; their validation with reverse docking and retrospective data mining

Abstract

Gefitinib, an EGFR tyrosine kinase inhibitor, is used as FDA approved drug in breast cancer and non-small cell lung cancer treatment. However, this drug has certain side effects and complications for which the underlying molecular mechanisms are not well understood. By systems biology based in silico analysis, we identified off-targets of gefitinib that might explain side effects of this drugs. The crystal structure of EGFR-gefitinib complex was used for binding pocket similarity searches on a druggable proteome database (Sc-PDB) by using IsoMIF Finder. The top 128 hits of putative off-targets were validated by reverse docking approach. The results showed that identified off-targets have efficient binding with gefitinib. The identified human specific off-targets were confirmed and further analyzed for their links with biological process and clinical disease pathways using retrospective studies and literature mining, respectively. Noticeably, many of the identified off-targets in this study were reported in previous high-throughput screenings. Interestingly, the present study reveals that gefitinib may have positive effects in reducing brain and bone metastasis, and may be useful in defining novel gefitinib based treatment regime. We propose that a system wide approach could be useful during new drug development and to minimize side effect of the prospective drug.

Detecting similar binding pockets to enable systems polypharmacology

“…To demonstrate the power of BioGPS, in Fig 1F we focus on two allosteric cavities that we found in the Epidermal Growth Factor Receptor (EGFR) and the Mitogen-Activated Protein Kinase 2 (MAPK2). While distant in the kinase phylogeny, off-target interactions between EGFR and MAPK2 have been previously detected in high-throughput kinase inhibition screens [24, 25]. The allosteric pockets that we found, when superimposed, show similar shape and non-bonded hydrophobic and polar patterns (S1F Fig), hinting towards a structural hypothesis for the MAPK2-EGFR cross-pharmacology.…”

Combined Menin and EGFR Inhibitors Synergize to Suppress Colorectal Cancer via EGFR-Independent and Calcium-Mediated Repression of SKP2 Transcription

“…Unlike EGFR antibodies, iEGFRs have not shown clinical efficacy in colorectal cancer; however, they are used clinically to successfully treat other cancers (13). As with most small molecules, iEGFRs have numerous effects within cells that are separate from their intended target (19)(20)(21). Although these effects may technically be referred to as "offtarget" effects, the contribution of these EGFR-independent effects may be an important mechanism contributing to the anticancer properties of these small molecules.…”

“…To investigate how menin inhibition synergizes with iEGFRs to repress colorectal cancer cells in an EGFR-independent manner, we sought to examine whether iEGFR-induced ER stress is involved (19)(20)(21)(22). Gefitinib alone was found to induce ER stress in HT-29 cells as it increases CHOP expression and XBP1 splicing (Fig.…”

“…iEGFRs such as gefitinib are effective at decreasing downstream EGFR signaling; however, these small molecules also regulate non-EGFR signaling pathways within cells in an "off-target" manner (19)(20)(21). One off-target process potentially associated with gefitinib is endoplasmic reticulum (ER) stress, as shown in intestinal epithelial cells (22).…”

EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP

“…To investigate the signals promoting OPC differentiation into myelinating OLs and how axon engagement is stimulated in the absence of neuronal feedback, here we used as a toolkit Clobetasol and Gefitinib, two drugs that have been shown to promote remyelination in vitro and/or in vivo [8,9,31]. Molecular studies have shown that Clobetasol acts essentially via the glucocorticoid receptor (GR) [9] and the Smo receptor [8,32] to promote MBP expression during OPC to OL differentiation, while Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) potentially acting on multiple receptors of the EGFR/ErbB family [33].…”