Received for publication January 27, 2005.
Revised May 26, 2005.
Accepted for publication May 26, 2005.

LY303511 Acts via PI3-kinase Independent Pathways to Inhibit Cell Proliferation via mTOR- and non-mTOR-dependent Mechanisms

Abstract

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 anti-neoplastic agent which, in complex with FKBP12, is a specific inhibitor of mTOR through interaction with its FRB domain, thereby causing G1 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 analogue, 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 G2/M progression, as well as G2/M-specific cyclins in A549 cells. Consistent with an additional mTOR-independent kinase target, LY303511 inhibited casein kinase 2 activity, a known regulator of G1 and G2/M progression. In addition to its anti-proliferative 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 anti-neoplastic actions that are independent of PI3K inhibition.

Key words: LY303511, cancer therapeutics, cell cycle, kinase, mammalian target of rapamycin, phosphatidylinositol 3 -kinase

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