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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

1
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
2
The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
3
Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(3), 1041; https://doi.org/10.3390/ijms21031041
Received: 16 January 2020 / Accepted: 30 January 2020 / Published: 4 February 2020
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. View Full-Text
Keywords: medicinal chemistry; cancer metabolism; amuvatinib; mechanistic target of rapamycin (mTOR); synthetic lethality medicinal chemistry; cancer metabolism; amuvatinib; mechanistic target of rapamycin (mTOR); synthetic lethality
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Marciano, R.; David, H.B.; Akabayov, B.; Rotblat, B. 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. Int. J. Mol. Sci. 2020, 21, 1041.

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