Anti-Proliferative Activity of an Unexpected mTOR Kinase Inhibitor

The second leading cause of death in the United States is cancer and more than one million Americans are diagnosed with cancer each year, with this number likely to increase as the population ages. There remains a need for effective therapeutics with improved safety profiles, and promising results have been obtained from targeting the phosphatidylinositol-3-kinase (PI3K) signalling cascade (including PI3K, AKT/PKB and mammalian target of rapamycin (mTOR/S6K) kinases) which is integral to the regulation of cell growth, protein synthesis and apoptosis in response to nutrients and mitogens, and which is frequently dysregulated in different cancers and other proliferative diseases. In particular, efforts have been directed at inhibiting specific kinases in this pathway as effective treatments for cancer, restenosis and autoimmune diseases and researchers at the National Heart, Lung and Blood Institute have recently shown that one of the 4H-1-benzopyran-4-one derivatives is unexpectedly an effective mTOR inhibitor.

Proof of concept data is available. This compound has been shown to attenuate tumor growth in an in vivo human xenograft PC-3 prostate tumor model, without observed toxicity. An improved therapeutic safety profile is suggested, as this compound was a weak inhibitor of PI3K. Further data indicate that inhibition of cell proliferation occurs through both mTOR-dependent and mTOR-independent mechanisms, suggesting a novel kinase inhibitor. Additionally, this cytostatic compound is shown to have an anti-inflammatory effect in peritoneal macrophages. Finally, this compound inhibits primary human smooth muscle cell proliferation in vitro, suggesting a possible role in the treatment of vascular restenosis.

This compound may therefore prove to be an effective anti-proliferative therapeutic. Available for licensing are methods of use directed to derivatives of 2-(4-piperazinyl)-substituted 4H-1-benzopyran-4-one compounds as antiproliferative, immunosuppressive and anti-neoplastic agents.