Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR

Qingsong Liu, Chunxiao Xu, Sivapriya Kirubakaran, Xin Zhang, Wooyoung Hur, Yan Liu, Nicholas P. Kwiatkowski, Jinhua Wang, Kenneth D. Westover, Peng Gao, Dalia Ercan, Mario Niepel, Carson C. Thoreen, Seong A. Kang, Matthew P. Patricelli, Yuchuan Wang, Tanya Tupper, Abigail Altabef, Hidemasa Kawamura, Kathryn D. HeldDanny M. Chou, Stephen J. Elledge, Pasi A. Janne, Kwok Kin Wong, David M. Sabatini, Nathanael S. Gray

Research output: Contribution to journalArticle

110 Scopus citations

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 EC50 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 includingATM(EC50, 28 nmol/L), ATR (EC50, 35 nmol/L), and DNA-PK (EC50, 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 wheremTOR signaling has a pathogenic role.

Original languageEnglish (US)
Pages (from-to)2574-2586
Number of pages13
JournalCancer research
Volume73
Issue number8
DOIs
StatePublished - Apr 15 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR'. Together they form a unique fingerprint.

  • Cite this

    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., ... Gray, N. S. (2013). Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR. Cancer research, 73(8), 2574-2586. https://doi.org/10.1158/0008-5472.CAN-12-1702