カワムラ　ヒデマサ   KAWAMURA Hidemasa   河村　英将    所属   埼玉医科大学  医学部 総合医療センター　放射線科(画像診断・核医学科、放射線腫瘍科)    職種   教授
論文種別	学術雑誌(原著)
言語種別	英語
査読の有無	査読あり
表題	Characterization of Torin2, an ATP-Competitive Inhibitor of mTOR, ATM, and ATR
掲載誌名	正式名：CANCER RESEARCH ISSNコード：0008-5472/1538-7445
出版社	AMER ASSOC CANCER RESEARCH
巻・号・頁	73(8),2574-2586頁
著者・共著者	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. Held,Danny M. Chou,Stephen J. Elledge,Pasi A. Janne,Kwok-Kin Wong,David M. Sabatini,Nathanael S. Gray
発行年月	2013/04
概要	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 including ATM(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 where mTOR signaling has a pathogenic role. Cancer Res; 73(8); 2574-86. (C) 2013 AACR.
DOI	10.1158/0008-5472.CAN-12-1702
PMID	23436801