Development of novel tetrazole-based pyruvate kinase M2 inhibitors targeting U87MG glioblastoma cells
Moumita Ghosh Chowdhury1, Saumya Kapoor1, Venkatesh Muthukumar1
1Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Ahmedabad (NIPER-A), Gandhinagar, Gujarat, India.
Abstract:
Glioblastoma (GB), the most aggressive and life-threatening primary brain tumor in adults, poses significant therapeutic challenges. Tumor pyruvate kinase M2 (PKM2) has been implicated in the proliferation and survival of glioma cells. In this study, we designed and synthesized a series of 23 novel tetrazole-based derivatives. The compounds were thoroughly characterized using 1H, 13C, 19F NMR, along with HRMS analysis. Among them, 1-(imidazo[1,2-a]pyrimidin-3-yl)-2-(5-(naphthalen-2-yl)-2H-tetrazol-2-yl)ethan-1-one (9b) exhibited potent and selective antiproliferative activity against U87MG glioma cells, with minimal effects on bEnd (brain endothelial cell line) non-glioma cells. It emerged as a potent PKM2 inhibitor, with an IC50 of 0.307 µM. Apoptosis assays and cell cycle analysis revealed that compound 9b induced early apoptosis and caused G1 phase arrest. A significant decrease in pyruvate concentration further suggested PKM2 inhibition. In silico studies confirmed the binding affinity to the PKM2 inhibitory site, and RT-PCR data demonstrated its inhibitory activity against PKM2. Additionally, it reduced lactate levels, indicating its potential impact on cellular metabolism. Collectively, these findings suggest that the most potent compound holds promise as a therapeutic candidate against GB.
Insights
A novel tetrazole derivative (9b) shows potent anticancer activity against glioblastoma by inhibiting pyruvate kinase M2 (PKM2), offering a promising new therapeutic strategy for this aggressive brain tumor.
Area of Science:
- Medicinal Chemistry
- Oncology
- Biochemistry
Background:
- Glioblastoma (GB) is a highly aggressive brain tumor with limited treatment options.
- Pyruvate kinase M2 (PKM2) plays a crucial role in glioma cell proliferation and survival, making it a potential therapeutic target.
Purpose of the Study:
- To design, synthesize, and evaluate novel tetrazole-based derivatives as potential glioblastoma therapeutics.
- To investigate the inhibitory effects of these compounds on PKM2 and their impact on glioma cell growth.
Main Methods:
- Synthesis and characterization of 23 novel tetrazole derivatives using NMR and HRMS.
- In vitro antiproliferative assays against U87MG glioma cells and bEnd non-glioma cells.
- Enzyme inhibition assays (PKM2), apoptosis assays, cell cycle analysis, in silico docking, and RT-PCR.
Main Results:
- Compound 9b demonstrated potent and selective antiproliferative activity against U87MG cells (IC50 = 0.307 µM) with minimal toxicity to normal brain endothelial cells.
- Compound 9b effectively inhibited PKM2, induced early apoptosis, caused G1 phase arrest in glioma cells, and reduced pyruvate and lactate levels.
- In silico studies confirmed favorable binding affinity to the PKM2 active site.
Conclusions:
- The novel tetrazole derivative 9b is a potent PKM2 inhibitor with significant antiproliferative activity against glioblastoma.
- Compound 9b exhibits promising therapeutic potential for glioblastoma treatment by targeting PKM2 and altering cellular metabolism.
