Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR. Liu, Q., Xu, C., Kirubakaran, S., Zhang, X., Hur, W., Liu, Y., Kwiatkowski, N. P., Wang, J., Westover, K. D., Gao, P., Ercan, D., Niepel, M., Thoreen, C. C., Kang, S. A., Patricelli, M. P., Wang, Y., Tupper, T., Altabef, A., Kawamura, H., Held, K. D., Chou, D. M., Elledge, S. J., Janne, P. A., Wong, K., Sabatini, D. M., & Gray, N. S. Cancer Research, 73(8):2574–2586, April, 2013.
doi  abstract   bibtex   
mTOR is a highly conserved serine/threonine protein kinase that serves as a central regulator of cell growth, survival, and autophagy. Deregulation of the PI3K/Akt/mTOR signaling pathway occurs commonly in cancer and numerous inhibitors targeting the ATP-binding site of these kinases are currently undergoing clinical evaluation. Here, we report the characterization of Torin2, a second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. Torin2 inhibited mTORC1-dependent T389 phosphorylation on S6K (RPS6KB1) with an EC(50) of 250 pmol/L with approximately 800-fold selectivity for cellular mTOR versus phosphoinositide 3-kinase (PI3K). Torin2 also exhibited potent biochemical and cellular activity against phosphatidylinositol-3 kinase-like kinase (PIKK) family kinases including ATM (EC(50), 28 nmol/L), ATR (EC(50), 35 nmol/L), and DNA-PK (EC(50), 118 nmol/L; PRKDC), the inhibition of which sensitized cells to Irradiation. Similar to the earlier generation compound Torin1 and in contrast to other reported mTOR inhibitors, Torin2 inhibited mTOR kinase and mTORC1 signaling activities in a sustained manner suggestive of a slow dissociation from the kinase. Cancer cell treatment with Torin2 for 24 hours resulted in a prolonged block in negative feedback and consequent T308 phosphorylation on Akt. These effects were associated with strong growth inhibition in vitro. Single-agent treatment with Torin2 in vivo did not yield significant efficacy against KRAS-driven lung tumors, but the combination of Torin2 with mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor AZD6244 yielded a significant growth inhibition. Taken together, our findings establish Torin2 as a strong candidate for clinical evaluation in a broad number of oncologic settings where mTOR signaling has a pathogenic role.
@article{liu_characterization_2013,
	title = {Characterization of {Torin2}, an {ATP}-competitive inhibitor of {mTOR}, {ATM}, and {ATR}},
	volume = {73},
	issn = {1538-7445},
	doi = {10.1158/0008-5472.CAN-12-1702},
	abstract = {mTOR is a highly conserved serine/threonine protein kinase that serves as a central regulator of cell growth, survival, and autophagy. Deregulation of the PI3K/Akt/mTOR signaling pathway occurs commonly in cancer and numerous inhibitors targeting the ATP-binding site of these kinases are currently undergoing clinical evaluation. Here, we report the characterization of Torin2, a second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. Torin2 inhibited mTORC1-dependent T389 phosphorylation on S6K (RPS6KB1) with an EC(50) of 250 pmol/L with approximately 800-fold selectivity for cellular mTOR versus phosphoinositide 3-kinase (PI3K). Torin2 also exhibited potent biochemical and cellular activity against phosphatidylinositol-3 kinase-like kinase (PIKK) family kinases including ATM (EC(50), 28 nmol/L), ATR (EC(50), 35 nmol/L), and DNA-PK (EC(50), 118 nmol/L; PRKDC), the inhibition of which sensitized cells to Irradiation. Similar to the earlier generation compound Torin1 and in contrast to other reported mTOR inhibitors, Torin2 inhibited mTOR kinase and mTORC1 signaling activities in a sustained manner suggestive of a slow dissociation from the kinase. Cancer cell treatment with Torin2 for 24 hours resulted in a prolonged block in negative feedback and consequent T308 phosphorylation on Akt. These effects were associated with strong growth inhibition in vitro. Single-agent treatment with Torin2 in vivo did not yield significant efficacy against KRAS-driven lung tumors, but the combination of Torin2 with mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor AZD6244 yielded a significant growth inhibition. Taken together, our findings establish Torin2 as a strong candidate for clinical evaluation in a broad number of oncologic settings where mTOR signaling has a pathogenic role.},
	language = {eng},
	number = {8},
	journal = {Cancer Research},
	author = {Liu, Qingsong and Xu, Chunxiao and Kirubakaran, Sivapriya and Zhang, Xin and Hur, Wooyoung and Liu, Yan and Kwiatkowski, Nicholas P. and Wang, Jinhua and Westover, Kenneth D. and Gao, Peng and Ercan, Dalia and Niepel, Mario and Thoreen, Carson C. and Kang, Seong A. and Patricelli, Matthew P. and Wang, Yuchuan and Tupper, Tanya and Altabef, Abigail and Kawamura, Hidemasa and Held, Kathryn D. and Chou, Danny M. and Elledge, Stephen J. and Janne, Pasi A. and Wong, Kwok-Kin and Sabatini, David M. and Gray, Nathanael S.},
	month = apr,
	year = {2013},
	keywords = {Adenosine Triphosphate, Animals, Antineoplastic Agents, Apoptosis, Ataxia Telangiectasia Mutated Proteins, Autophagy, Benzimidazoles, Binding, Competitive, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, Cell cycle, DNA-Binding Proteins, Disease Models, Animal, Drug Synergism, Humans, Kinetics, Lung Neoplasms, Mice, Naphthyridines, Protein Binding, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases, Tumor Burden, Tumor Suppressor Proteins, Xenograft Model Antitumor Assays, ras Proteins},
	pages = {2574--2586},
}
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