Preclinical validation of tetrahydroquinoline derivatives as EGFR inhibitor inducing glioblastoma cell death

Abstract

Glioblastoma multiforme, a malignant brain tumor has a dismal prognosis and lacks effective treatment. Epidermal growth factor receptor (EGFR) is an attractive drug target for GBM treatment, yet no therapeutic effect has been reported. Here, we have deepened our studies on a recently described EGFR inhibitor, a tetrahydroquinoline-derived triarylmethane, 2-((1,2,3,4-tetrahydroquinolin-8-yl)(4-(trifluoromethyl)phenyl)methyl)phenol (THQPMP), showing a potential cytotoxicity activity against GBM cells LN229 and SNB19. THQPMP exhibits a strong binding affinity to the EGFR receptor of -6.92 kcal/mol, which interacts with 12 amino acid residues. The stable interaction of THQPMP-EGFR complex was validated by molecular simulations dynamics lasting 200 ns. The statistical parameters of partial least squares regression (PLS) revealed robust internal predictive capacity for the Gaussian-based QSAR model developed. The half maximum inhibitory concentration (IC50) for THQPMP and gefitinib was established to be 40.6 µM and 46 µM for LN229 cells and 38.3 µM and 68 µM for SNB19 cells, respectively. SiRNA transfection assay confirmed the specific interaction of THQPMP with EGFR, thus modulating the downstream signaling cascade and inducing cell death in GBM. Furthermore, THQPMP prompted cell cycle arrest at S phase and observed to induce a negligible fold of intracellular calcium level, thereby leading to GBM cell death via a calcium-independent signaling mechanism. A comprehensive ADME analysis was performed, predicting the physicochemical, absorption, distribution, metabolism, and excretion parameters of THQPMP, therefore elucidating its pharmacokinetic and drug likeness properties. THQPMP was validated to cross the blood-brain barrier with moderate permeability. Overall, THQPMP has shown efficient preclinical activity against GBM by modulating EGFR signaling pathways, warranting further in vivo validation for phase clinical trials.