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J. Biol. Chem., Vol. 282, Issue 33, 24463-24470, August 17, 2007

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Inhibition of Mammalian Target of Rapamycin Signaling by 2-(Morpholin-1-yl)pyrimido[2,1-]isoquinolin-4-one^*

Lisa M. Ballou¹, Elzbieta S. Selinger, Jun Yong Choi, Dale G. Drueckhammer, and Richard Z. Lin^¶||

From the Department of Medicine, the Department of Chemistry and the Institute of Chemical Biology & Drug Discovery, and the ^¶Department of Physiology and Biophysics and the Institute of Molecular Cardiology, Stony Brook University, Stony Brook, New York 11794 and the ^||Department of Veterans Affairs Medical Center, Northport, New York 11768

Signaling through the mammalian target of rapamycin (mTOR) is hyperactivated in many human tumors, including hamartomas associated with tuberous sclerosis complex (TSC). Several small molecules such as LY294002 inhibit mTOR kinase activity, but they also inhibit phosphatidylinositol 3-kinase (PI3K) at similar concentrations. Compound 401 is a synthetic inhibitor of DNA-dependent protein kinase (DNA-PK) that also targets mTOR but not PI3K in vitro (Griffin, R. J., Fontana, G., Golding, B. T., Guiard, S., Hardcastle, I. R., Leahy, J. J., Martin, N., Richardson, C., Rigoreau, L., Stockley, M., and Smith, G. C. (2005) J. Med. Chem. 48, 569-585). We used 401 to test the cellular effect of mTOR inhibition without the complicating side effects on PI3K. Treatment of cells with 401 blocked the phosphorylation of sites modified by mTOR-Raptor and mTOR-Rictor complexes (ribosomal protein S6 kinase 1 Thr³⁸⁹ and Akt Ser⁴⁷³, respectively). By contrast, there was no direct inhibition of Akt Thr³⁰⁸ phosphorylation, which is dependent on PI3K. Similar effects were also observed in cells that lack DNA-PK. The proliferation of TSC1^-/- fibroblasts was inhibited in the presence of 401, but TSC1^+/+ cells were resistant. In contrast to rapamycin, long-term treatment of TSC1^-/- cells with 401 did not up-regulate phospho-Akt Ser⁴⁷³. Because increased Akt activity promotes survival, this may explain why the level of apoptosis was increased in the presence of 401 but not rapamycin. These results suggest that mTOR kinase inhibitors might be more effective than rapamycins in controlling the growth of TSC hamartomas and other tumors that depend on elevated mTOR activity.

Received for publication, June 8, 2007

^* This work was supported in part by Carol M. Baldwin Breast Cancer Research Awards (to L. M. B. and R. Z. L.), grants from the Dept. of Veterans Affairs (to R. Z. L.), and National Institutes of Health Grants DK62722 (to R. Z. L.) and DK59568 (to D. G. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medicine, Division of Hematology/Oncology, Stony Brook University, Stony Brook, NY 11794-8151. Tel.: 631-444-2059; Fax: 631-444-7530; E-mail: lisa.ballou{at}sunysb.edu.

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