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Discovery of 2-Pyrazolines That Inhibit the Phosphorylation of STAT3 as Nanomolar Cytotoxic Agents
Tejaswini P Siddappa1, Akshay Ravish1, Zhang Xi2
1Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore, Karnataka 570006, India.
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.
Insights
New imidazopyridine clubbed 2-pyrazolines were synthesized to target STAT3 phosphorylation in estrogen receptor-positive breast cancer (ER+ BC). Compound 3p significantly reduced ER+ BC cell viability and STAT3 phosphorylation, showing therapeutic potential.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Signal transducer and activator of transcription 3 (STAT3) is a validated cancer target, implicated in breast cancer (BC) development, progression, and immune evasion.
- Previous research identified imidazo[1,2-a]pyridine tethered 2-pyrazolines (ITPs) as inhibitors of STAT3 phosphorylation in estrogen receptor-positive (ER+) BC cells.
Purpose of the Study:
- To synthesize and evaluate novel imidazo[1,2-a]pyridine clubbed 2-pyrazolines and their amide derivatives for ER+ BC treatment.
- To investigate the mechanism of action, focusing on STAT3 phosphorylation inhibition.
Main Methods:
- Synthesis of a new library of imidazo[1,2-a]pyridine clubbed 2-pyrazolines (compounds 2a-o) and amide derivatives (compounds 3a-af).
- Evaluation of cell viability inhibition using IC50 values.
- In silico molecular docking simulations to predict binding affinity to STAT3.
- Western blot analysis to assess the effect on STAT3 phosphorylation at Tyr705.
Main Results:
- Compounds 3n and 3p demonstrated significant efficacy in reducing ER+ BC cell viability, with IC50 values of 55 nM and 15 nM, respectively.
- Molecular docking predicted strong binding of compound 3p to STAT3 (binding energy of -9.56 kcal/mol).
- Western blot analysis confirmed that compound 3p treatment decreased phosphorylated STAT3 levels in ER+ BC cells.
Conclusions:
- The synthesized imidazopyridine clubbed 2-pyrazolines show significant potential for reducing ER+ BC cell viability.
- Compound 3p is identified as a promising novel inhibitor of STAT3 phosphorylation, warranting further investigation for therapeutic development in ER+ BC.
