The Amuvatinib Derivative, N-(2H-1,3-Benzodioxol-5-yl)-4-{thieno[3,2-d]pyrimidin-4-yl}piperazine-1-carboxamide, Inhibits Mitochondria and Kills Tumor Cells under Glucose Starvation
Open Access
- 4 February 2020
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 21 (3), 1041
- https://doi.org/10.3390/ijms21031041
Abstract
Glucose levels inside solid tumors are low as compared with normal surrounding tissue, forcing tumor cells to reprogram their metabolism to adapt to such low glucose conditions. Unlike normal tissue, tumor cells experience glucose starvation, making the targeting of pathways supporting survival during glucose starvation an interesting therapeutic strategy in oncology. Using high-throughput screening, we previously identified small molecules that selectively kill cells exposed to glucose starvation. One of the identified compounds was the kinase inhibitor amuvatinib. To identify new molecules with potential antineoplastic activity, we procured 12 amuvatinib derivatives and tested their selective toxicity towards glucose-starved tumor cells. One of the amuvatinib derivatives, N-(2H-1,3-benzodioxol-5-yl)-4-{thieno[3,2-d]pyrimidin-4-yl}piperazine-1-carboxamide, termed compound 6, was found to be efficacious in tumor cells experiencing glucose starvation. In line with the known dependence of glucose-starved cells on the mitochondria, compound 6 inhibits mitochondrial membrane potential. These findings support the concept that tumor cells are dependent on mitochondria under glucose starvation, and bring forth compound 6 as a new molecule with potential antitumor activity for the treatment of glucose-starved tumors.Keywords
This publication has 21 references indexed in Scilit:
- Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?Nature Reviews Cancer, 2016
- MYC, Metabolism, and CancerCancer Discovery, 2015
- Epigenetic Therapy for Solid Tumors: Highlighting the Impact of Tumor HypoxiaGenes, 2015
- Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanidesNature, 2014
- Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose MetabolismCell, 2012
- Glucose Addiction of TSC Null Cells Is Caused by Failed mTORC1-Dependent Balancing of Metabolic Demand with SupplyMolecular Cell, 2010
- Quantitative Metabolome Profiling of Colon and Stomach Cancer Microenvironment by Capillary Electrophoresis Time-of-Flight Mass SpectrometryCancer Research, 2009
- Chemical Genomics Identifies the Unfolded Protein Response as a Target for Selective Cancer Cell Killing during Glucose DeprivationCancer Research, 2009
- The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid β-oxidationOncogene, 2005
- TSC2 Mediates Cellular Energy Response to Control Cell Growth and SurvivalCell, 2003