2. Academic Validation
  3. PT109, a novel multi-kinase inhibitor suppresses glioblastoma multiforme through cell reprogramming: Involvement of PTBP1/PKM1/2 pathway

PT109, a novel multi-kinase inhibitor suppresses glioblastoma multiforme through cell reprogramming: Involvement of PTBP1/PKM1/2 pathway

  • Eur J Pharmacol. 2022 Apr 5:920:174837. doi: 10.1016/j.ejphar.2022.174837.
Yang Yang 1,  Yalin Tu 2,  Junfeng Lu 2,  Qiuhe Chen 2,  Zeyu Zhu 2,  Weijia Peng 2,  Wenbo Zhu 3,  Shijun Wen 4,  Ji Zhang 4,  Wei Yin 5,  Rongbiao Pi 6
Affiliations

Affiliations

  • 1 School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China.
  • 2 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
  • 3 Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510089, China.
  • 4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 5 Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510089, China. Electronic address: yinwei@mail.sysu.edu.cn.
  • 6 School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China; School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China; International Joint Laboratory of Novel Anti-Dementia Drugs of Guangzhou, Guangzhou, 510006, China; National and Local United Engineering Lab of Drugability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, 510006, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: pirb@mail.sysu.edu.cn.
PMID: 35218719 DOI: 10.1016/j.ejphar.2022.174837
Abstract

Glioblastoma multiforme (GBM) is the most prevalent type and lethal form of primary malignant brain tumor, accounting for about 40-50% of intracranial tumors and without effective treatments now. Cell reprogramming is one of the emerging treatment approaches for GBM, which can reprogram glioblastomas into non-tumor cells to achieve therapeutic effects. However, anti-GBM drugs through reprogramming can only provide limited symptom relief, and cannot completely cure GBM. Here we showed that PT109, a novel multi-kinase inhibitor, suppressed GBM's proliferation, colony formation, migration and reprogramed GBM into oligodendrocytes. Analysis of quantitative proteomics data after PT109 administration of human GBM cells showed significant influence of energy metabolism, cell cycle, and immune system processes of GBM-associated protein. Metabolomics analysis showed that PT109 improved the aerobic respiration process in glioma cells. Meanwhile, we found that PT109 could significantly increase the ratio of Pyruvate Kinase M1/2 (PKM1/2) by reducing the level of polypyrimidine tract-binding protein 1 (PTBP1). Altogether, this work developed a novel anti-GBM small molecule PT109, which reprogramed GBM into oligodendrocytes and changed the metabolic pattern of GBM through the PTBP1/PKM1/2 pathway, providing a new strategy for the development of anti-glioma drugs.

Keywords

Glioblastoma multiforme; PT109; PTBP1; Reprogramming; Warburg effect.

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