Discovery of 2-Pyrazolines That Inhibit the Phosphorylation of STAT3 as Nanomolar Cytotoxic Agents.

Abstract

STAT3 has emerged as a validated target in cancer, being functionally associated with breast cancer (BC) development, growth, resistance to chemotherapy, metastasis, and evasion of immune surveillance. Previously, a series of compounds consisting of imidazo[1,2-a]pyridine tethered 2-pyrazolines (referred to as ITPs) were developed that inhibit STAT3 phosphorylation in estrogen receptor-positive (ER+) BC cells. Herein, a new library of derivatives consisting of imidazo[1,2-a]pyridine clubbed 2-pyrazolines 2(a-o) and its amide derivatives 3(a-af) have been synthesized. Among these derivatives, 3n and 3p displayed efficacy to reduce ER+ BC cell viability, with IC₅₀ values of 55 and 15 nM, respectively. Molecular docking simulations predicted that compound 3p bound to STAT3 protein, with a binding energy of -9.56 kcal/mol. Using Western blot analysis, it was demonstrated that treatment of ER+ BC cells with compound 3p decreased the levels of phosphorylated STAT3 at the Tyr705 residue. In conclusion, this investigation presents the synthesis of imidazopyridine clubbed 2-pyrazolines that exhibit significant efficacy in reducing viability of ER+ BC cells. In silico docking and Western blot analyses together support compound 3p as a promising novel inhibitor of STAT3 phosphorylation, suggesting its potential as a valuable candidate for further therapeutic development.