Targeting telomerase for lung cancer: design and synthesis of acridine hybrids with in vitro and in vivo evaluation

Abstract

Lung cancer remains the leading cause of cancer-related deaths worldwide, emphasizing the need for effective targeted therapeutics. Telomerase, which is aberrantly activated in most lung tumors, is an attractive molecular target; however, the clinical translation of its inhibitors has been limited. In this study, we employed a rational design approach that integrated pharmacophore modeling, virtual screening, QSAR, and molecular docking to develop acridine–thiadiazole hybrids as potential telomerase inhibitors. Guided by pharmacophore-based virtual screening and 3D-QSAR studies, 32 derivatives were synthesized through an optimized route for synthesis and evaluated for anticancer activity. Several compounds displayed potent sub-micromolar cytotoxicity against A549 lung cancer cells with minimal toxicity toward Vero cells. Among them, compound 28 emerged as the most potent, exhibiting nanomolar activity and strong telomerase inhibition, while compounds 21, 29, and 39 also demonstrated significant efficacy. Mechanistic studies confirmed apoptosis induction, inhibition of clonogenic survival, and telomerase suppression. In vivo evaluation in a benzo[a]pyrene-induced lung cancer model further validated the therapeutic potential of these hybrids, showing reduced tumor burden, restoration of antioxidant balance, and preservation of lung architecture. Collectively, these findings highlight acridine–thiadiazole hybrids, particularly compound 28, as promising, selective telomerase inhibitors for lung cancer therapy.