Editorial [ Hot Topic: Novel Medicinal Chemistry Approaches to New Anti-cancer Agents (Guest Editor: Diane H. Boschelli) ]

In 1971 President Richard Nixon declared a “War on Cancer” and requested an allocation of 100 million dollars from the US Congress to find a cure. In spite of the vast research efforts since then, the American Cancer Society estimates that in the United States 565,650 people will die from cancer this year and 1,437,000 new cancers will be diagnosed. The picture worldwide is similarly gloomy with an estimated 7.6 million cancer deaths and 12 million new cases for 2007. Therefore, although there are almost 200 drugs currently approved for the treatment of cancer, there remains a large unmet need for new therapeutic agents. This special issue of Current Topics in Medicinal Chemistry is devoted to the review of some exciting new oncology targets and the progress that has been made on identifying small molecule inhibitors of these targets. The issue begins with an overview of potential anti-cancer therapeutics that can inhibit some key proteins that control the activity of numerous signaling pathways implicated in tumor development. In the first article, Moradei and coworkers at MethylGene discuss inhibitors of histone deacetylase (HDAC), enzymes whose inhibition results in cell cycle arrest or apoptosis in cancer cells. The second article by Drysdale and Brough of Vernalis focuses on new inhibitors of heat shock protein 90 (HSP90), a molecular chaperone whose function is to stabilize cellular proteins, many of which are oncogenes. The next two reviews describe inhibitors of targets with less pleiotropic but nonetheless profound effects on tumor cells. The first is an update on nonsteroidal aromatase inhibitors for the treatment of hormone-dependent breast cancer by Gobbi and coworkers at the University of Bologna, who also discuss some new multi-targeted compounds. This paper is followed by a discussion from Knight and Parrish of GlaxoSmithKline on inhibitors of the mitotic kinesin spindle protein (KSP), an intracellular motor protein whose inhibition results in mitotic arrest. Imatinib, being the first small molecule kinase inhibitor to reach the market, was the poster child of oncology drug discovery in the last decade. Imatinib inhibits the activity of Abl kinase, and the presence of an activated form of this kinase is the hallmark of chronic myelogenous leukemia (CML). Imatinib is highly efficacious in treating early stage CML patients but resistance to the drug can occur, often as the result of mutations in the kinase domain of Abl. In the penultimate review, Noronha and coworkers at TargeGen describe efforts to develop new Abl inhibitors including those that can also inhibit the most clinically refractory mutation, that of threonine 315 to isoleucine. In the final article which focuses on a single class of Src kinase inhibitors, the 3-quinolinecarbonitriles, I describe how optimization of this series by Wyeth resulted in a dual inhibitor of both Src and Abl kinases that is currently in clinical trials for the treatment of CML. Many thanks to all the authors for their comprehensive contributions and to Allen Reitz for the invitation to serve as the Guest Editor for this issue. Our aim was to present a cross section of the different approaches being used to combat cancer and we hope that readers will find this issue to be informative and perhaps even inspiring. The ultimate goal however remains winning the war.