PMID- 22305748 OWN - NLM STAT- MEDLINE DCOM- 20120521 LR - 20211203 IS - 1873-2968 (Electronic) IS - 0006-2952 (Linking) VI - 83 IP - 9 DP - 2012 May 1 TI - Inhibition of tumor cell growth, proliferation and migration by X-387, a novel active-site inhibitor of mTOR. PG - 1183-94 LID - 10.1016/j.bcp.2012.01.019 [doi] AB - The mammalian target of rapamycin (mTOR), is deregulated in about 50% of human malignancies and exists in two complexes: mTORC1 and mTORC2. Rapalogs partially inhibit mTORC1 through allosteric binding to mTORC1 and their efficacy is modest as a cancer therapy. A few mTOR kinase inhibitors that inhibit both mTORC1 and mTORC2 have been reported to possess potent anticancer activities. Herein, we designed and synthesized a series of pyrazolopyrimidine derivatives targeting mTOR kinase domain and X-387 was identified as a promising lead. X-387 selectively inhibited mTOR in an ATP-competitive manner while sparing a panel of kinases from the PIKK family. X-387 blocked mTORC1 and mTORC2-mediacted signaling pathway in cell lines with activated mTOR signaling and in rapamycin-resistant cells. Specifically, X-387 inhibited phosphorylation of AKT at T308, which is thought to be a target of PDK1 but not mTOR. Such activity was not due to inhibition of PI3K since X-387 did not inhibit translocation of AKT to the cell membrane. X-387 induced autophagy as observed for other mTOR inhibitors, while induced autophagy is pro-survival since concurrent inhibition of autophagy by 3-MA reinforced the antiproliferative activity of mTOR inhibitors. X-387 also inhibited cell motility, which is associated with decrease in activity of small GTPases such as RhoA, Rac1 and Cdc42. Taken together, X-387 is a promising compound lead targeting mTOR and with a wide spectrum anticancer activity among tumor cell lines. The data also underscores the complexity of the mTOR signaling pathways which are far from being understood. CI - Copyright (c) 2012 Elsevier Inc. All rights reserved. FAU - Chen, Si-meng AU - Chen SM AD - Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, PR China. FAU - Liu, Jia-li AU - Liu JL FAU - Wang, Xiang AU - Wang X FAU - Liang, Chris AU - Liang C FAU - Ding, Jian AU - Ding J FAU - Meng, Ling-hua AU - Meng LH LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120126 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - 0 (Antineoplastic Agents) RN - 0 (Phenylurea Compounds) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidines) RN - 0 (RAC1 protein, human) RN - 0 (X-387) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Oncogene Protein v-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.6.5.2 (cdc42 GTP-Binding Protein) RN - EC 3.6.5.2 (rac1 GTP-Binding Protein) RN - EC 3.6.5.2 (rhoA GTP-Binding Protein) SB - IM MH - Adenosine Triphosphate/metabolism MH - Antineoplastic Agents/*pharmacology MH - Autophagy/drug effects MH - Binding, Competitive MH - Catalytic Domain MH - Cell Line, Tumor MH - Cell Movement/drug effects MH - Cell Proliferation/drug effects MH - Cell Size/drug effects MH - Drug Screening Assays, Antitumor MH - G1 Phase Cell Cycle Checkpoints/drug effects MH - Humans MH - Neoplasms/*drug therapy/metabolism/pathology MH - Oncogene Protein v-akt/metabolism MH - Phenylurea Compounds/*pharmacology MH - Phosphatidylinositol 3-Kinases/metabolism MH - Phosphorylation/drug effects MH - Protein Kinase Inhibitors/*pharmacology MH - Pyrimidines/*pharmacology MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism MH - cdc42 GTP-Binding Protein/metabolism MH - rac1 GTP-Binding Protein MH - rhoA GTP-Binding Protein EDAT- 2012/02/07 06:00 MHDA- 2012/05/23 06:00 CRDT- 2012/02/07 06:00 PHST- 2011/12/07 00:00 [received] PHST- 2012/01/14 00:00 [revised] PHST- 2012/01/17 00:00 [accepted] PHST- 2012/02/07 06:00 [entrez] PHST- 2012/02/07 06:00 [pubmed] PHST- 2012/05/23 06:00 [medline] AID - S0006-2952(12)00066-4 [pii] AID - 10.1016/j.bcp.2012.01.019 [doi] PST - ppublish SO - Biochem Pharmacol. 2012 May 1;83(9):1183-94. doi: 10.1016/j.bcp.2012.01.019. Epub 2012 Jan 26.