2. Academic Validation
  3. Preclinical validation of tetrahydroquinoline derivatives as EGFR inhibitor inducing glioblastoma cell death

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

  • Eur J Pharm Sci. 2026 Mar 14:221:107503. doi: 10.1016/j.ejps.2026.107503.
Akshaya Murugesan 1,  Saravanan Konda Mani 2,  Aleksei Smirnov 3,  Shabnaz Koochakkhani 4,  Sabarish Nambi Narayanan 4,  Daniela S N Branco 5,  Sandhanasamy Devanesan 6,  Mohammad Ahmad Wadaan 6,  Nuno R Candeias 7,  Meenakshisundaram Kandhavelu 8
Affiliations

Affiliations

  • 1 Molecular Signaling Group, Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland; Tays Cancer Center, Tampere University, Hospital, P.O. Box 553, 33101 Tampere, Finland.
  • 2 Centre for Research and Innovation, AMET University, East Coast Road, Kanathur, Chennai, Tamil Nadu, 603112, India.
  • 3 Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, 62032 Camerino, Italy.
  • 4 Molecular Signaling Group, Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland.
  • 5 LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.
  • 6 Bioproducts Research Chair, Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia.
  • 7 LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal; Faculty of Engineering and Natural Sciences, Tampere University, Korkeakoulunkatu 8, 33101 Tampere, Finland.
  • 8 Molecular Signaling Group, Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland; Tays Cancer Center, Tampere University, Hospital, P.O. Box 553, 33101 Tampere, Finland. Electronic address: [email protected].
PMID: 41839309 DOI: 10.1016/j.ejps.2026.107503
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.

Keywords

Anticancer; BBB; EGFR; Glioblastoma; Tetrahydroquinoline.

Figures
Products