PMID- 15923340 OWN - NLM STAT- MEDLINE DCOM- 20051021 LR - 20211203 IS - 0022-3565 (Print) IS - 0022-3565 (Linking) VI - 314 IP - 3 DP - 2005 Sep TI - LY303511 (2-piperazinyl-8-phenyl-4H-1-benzopyran-4-one) acts via phosphatidylinositol 3-kinase-independent pathways to inhibit cell proliferation via mammalian target of rapamycin (mTOR)- and non-mTOR-dependent mechanisms. PG - 1134-43 AB - Mammalian target of rapamycin (mTOR), a serine/threonine kinase, regulates cell growth and proliferation in part via the activation of p70 S6 kinase (S6K). Rapamycin is an antineo-plastic agent that, in complex with FKBP12, is a specific inhibitor of mTOR through interaction with its FKBP12-rapamycin binding domain, thereby causing G(1) cell cycle arrest. However, cancer cells often develop resistance to rapamycin, and alternative inhibitors of mTOR are desired. 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) blocks mTOR kinase activity, but it also inhibits phosphatidylinositol 3-kinase (PI3K), an enzyme that regulates cellular functions other than proliferation. We hypothesized that a close structural analog, 2-piperazinyl-8-phenyl-4H-1-benzopyran-4-one (LY303511) might inhibit mTOR-dependent cell proliferation without unwanted effects on PI3K. In human lung epithelial adenocarcinoma (A549) cells, LY303511, like rapamycin, inhibited mTOR-dependent phosphorylation of S6K, but not PI3K-dependent phosphorylation of Akt. LY303511 blocked proliferation in A549 as well as in primary pulmonary artery smooth muscle cells, without causing apoptosis. In contrast to rapamycin, LY303511 reduced G(2)/M progression as well as G(2)/M-specific cyclins in A549 cells. Consistent with an additional mTOR-independent kinase target, LY303511 inhibited casein kinase 2 activity, a known regulator of G(1) and G(2)/M progression. In addition to its antiproliferative effect in vitro, LY303511 inhibited the growth of human prostate adenocarcinoma tumor implants in athymic mice. Given its inhibition of cell proliferation via mTOR-dependent and independent mechanisms, LY303511 has therapeutic potential with antineoplastic actions that are independent of PI3K inhibition. FAU - Kristof, Arnold S AU - Kristof AS AD - Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. arnold.kristof@muhc.mcgill.ca FAU - Pacheco-Rodriguez, Gustavo AU - Pacheco-Rodriguez G FAU - Schremmer, Bruno AU - Schremmer B FAU - Moss, Joel AU - Moss J LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, P.H.S. DEP - 20050527 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (Antineoplastic Agents) RN - 0 (Chromones) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Piperazines) RN - 0 (Proto-Oncogene Proteins) RN - 154447-38-8 (LY 303511) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (AKT1 protein, human) RN - EC 2.7.11.1 (Casein Kinase II) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Antineoplastic Agents/*pharmacology MH - Casein Kinase II/metabolism MH - Cell Cycle/drug effects MH - Cell Proliferation/drug effects MH - Cells, Cultured MH - Chromones/*pharmacology MH - Humans MH - Male MH - Mice MH - Muscle, Smooth, Vascular/cytology/drug effects/metabolism MH - Phosphatidylinositol 3-Kinases/*physiology MH - Phosphoinositide-3 Kinase Inhibitors MH - Phosphorylation MH - Piperazines/*pharmacology MH - Prostatic Neoplasms/drug therapy MH - Protein Kinases/*physiology MH - Protein Serine-Threonine Kinases/metabolism MH - Proto-Oncogene Proteins/metabolism MH - Proto-Oncogene Proteins c-akt MH - Pulmonary Artery/drug effects MH - Ribosomal Protein S6 Kinases/metabolism MH - TOR Serine-Threonine Kinases EDAT- 2005/06/01 09:00 MHDA- 2005/10/22 09:00 CRDT- 2005/06/01 09:00 PHST- 2005/06/01 09:00 [pubmed] PHST- 2005/10/22 09:00 [medline] PHST- 2005/06/01 09:00 [entrez] AID - jpet.105.083550 [pii] AID - 10.1124/jpet.105.083550 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2005 Sep;314(3):1134-43. doi: 10.1124/jpet.105.083550. Epub 2005 May 27.