Cell Cycle Kinases as Therapeutic Targets for Cancer

Newswise — A comprehensive overview that explores the prospects and progress of synthetic inhibitors to target cell cycle kinases in cancer forecasts that "novel compounds with increased potency, improved kinase specificity and favorable drug like properties will soon be available for clinical evaluation."

The article, which is featured in the July 2009 online issue of Nature Reviews/Drug Discovery, was written by Antonio Giordano, M.D., Ph.D., the Director of the Sbarro Institute for Cancer Research and Molecular Medicine, the Director of the Center for Biotechnology at Temple University in Philadelphia, PA and a 'Chiara fama' Professor in the Department of Pathology & Oncology at the University of Siena in Siena, Italy and Silvia Lapenna, Ph.D., a member of CROM (Center for Oncology Research) in Mercogliano, Italy.

Cell cycle kinases are proteins that orchestrate the complex events that regulate the proper division of our cells. When genes mutate in cancer, cell cycle kinases and/or their protein regulators may be dysregulated, leading to aberrant cell division and uncontrolled proliferation of cells, both prime hallmarks of human cancer.

While numerous small-molecule inhibitors have been developed to target cell cycle kinases, none has yet been approved for commercial clinical use. The search for synthetic inhibitors of protein kinases as anticancer drugs has been boosted recently by successful approval of a number of molecules that target tyrosine kinases, such as the BCR-ABL protein kinases inhibitor imatinib (Gleevec; Novartis) for the treatment of chronic myelogenous leukemia.

"Future approaches should combine the lessons learned from early work using small-molecule inhibitors with the recent increased understanding of the deregulation of cell cycle protein kinases in cancer," says Dr. Giordano. "Chemical inhibition has emerged as a powerful approach to advance our understanding of these kinases and numerous inhibitors are being developed as potential anticancer drugs."

In the review, Dr. Lapenna and Dr. Giordano describe the biological activities of several promising protein kinases involved in the regulation of the cell cycle that may offer new therapeutic targets. These include cyclin dependent kinases (CDKs), DNA-damage checkpoint kinases and spindle-assembly checkpoint regulators, aurora kinases and polo-like kinases, each of which often operate abnormally in cancerous cells.

The researchers note that CDK serine-threonine protein kinases have received particular attention as possible therapeutic targets, owing to their crucial role in cell proliferation and frequent upregulation in human cancer.

While first generation CDK inhibitors have exhibited only minor efficacy in clinical trials, the authors say that several second-generation compounds have shown more potency and/or specificity than earlier inhibitors. Also, genetic studies have revealed valuable information for the validation of specific CDK variants as potential targets in cancer therapy. By selectively inhibiting certain CDKs, the writers hold that it may be possible to limit the proliferation of specific tumor cells which survival depends specifically on the expression and activation of these CDKs.

The authors also discuss promising emerging strategies for therapeutic intervention based on inhibiting kinases that signal DNA damage to enhance cancer cell sensitivity to genotoxic agents, and targeting kinases that control mitosis to selectively kill tumour cells.

Sbarro Health Research Organization (www.shro.org) is committed to excellence in basic genetic research to cure and diagnose cancer, cardiovascular diseases, diabetes and other chronic illnesses and to foster the training of young doctors in a spirit of professionalism and humanism. The Sbarro Health Research Organization funds the Sbarro Institute for Cancer Research and Molecular Medicine, located at Temple University in Philadelphia, PA.

The Human Health Foundation (www.hhfonlus.org), a nonprofit organization, develops and funds biomedical research and health education initiatives in Italy. HHF is located in Terni, Italy.