Preface [Hot Topic: Anti-Cancer Agents (Executive Editors: A.P. Kozikowski and M. Pellecchia)]

This issue of Current Pharmaceutical Design is dedicated to the characterization of potential anticancer agents. In this respect, a plethora of approaches are currently being investigated to design or discover novel compounds that are capable to effectively and selectively kill cancer cells, sparing normal cells. These approaches vary from the selection of possible cancer-specific protein targets and the design and synthesis of their potential inhibitors, to the selection and chemical modification of natural products or known cytotoxic agents with anticancer activity, to computational approaches, just to mention a few. Thought not nearly close to be a comprehensive review of the possible current approaches to cancer drug discovery, the four reviews reported here represents excellent examples of as many different methodologies. The first article by Kazuhiro Irie, Yu Nakagawa and Hajime Ohigashi [1] reports on the derivation of novel compounds based on indolactams and benzolactams targeting protein kinase C (PKC) isozymes. As described in the review, the design of agents with not only PKC isozyme selectivity but also the C1 domain selectivity of each PKC isozyme is of fundamental importance for understanding the precise mechanism of tumor promotion and developing novel therapeutic compounds. An emerging field in cancer drug discovery is the search for compounds capable to sensitize cancer cells to chemotherapy (chemosensitizers). Most of the activities in this area are related to the inhibition of anti-apoptotic Bcl-2 family proteins that, over expressed in most human cancers, prevent cancer cells to die despite radiation or chemotherapy. The review by Maurizio Pellecchia and John Reed [2] reports on recent findings that link anticancer and chemopreventive activity of certain natural polyphenols to their direct inhibition of anti-apoptotic Bcl-2 family proteins. A discussion on possible improvements of such compounds as well as their potential uses as chemosensitizers in combination therapy is reported. The search for novel anticancer agents often requires the synthesis of many compounds or the screen of large libraries of compounds. Both approaches are costly and time consuming. Computational chemistry may reduce these efforts by increasing the likelihood of a positive outcome from such studies. In the review by Steven Ren and Eric Lien [3] the contributions of different physicochemical parameters to the tumor cell growth inhibitory activities of several anticancer agents are evaluated by a quantitative structure-activity relationship approach (QSAR). Intriguing results are shown demonstrating that compounds' molecular weight (MW) is the most important contributor to the tumor cell growth inhibitory activities among the physicochemical parameters examined, indicating that MW should be taken into account in anticancer drug design. Also, the results obtained may be used as a filter to design smaller focused libraries from a large number of compounds to be experimentally tested. A traditional way to develop anticancer compounds capable of discriminating between cancer and normal cells is to exploit protein targets involved in cell division. The crucial role played by Tubulin in cell-division has made this protein a target for natural product-based chemical defense mechanisms. Such antimitotic compounds have also great potential as anticancer agents. Peter Wipf, Jonathan Reevs and Billy Day [4] report on elegant synthetic approaches to derive novel analogues of the antimitotic marine natural product curacin A aimed at improving anticancer activity and chemical-physical properties. Low water-solubility and lack of chemical stability have prevented the use of curacin A for clinical development. Therefore the synthetic schemes and analogs proposed in the review might prove very useful in probing the efficacy of such agents in cancer therapy. Overall, the current issue addresses in remarkable detail different aspects of current approaches to cancer drug discovery. We thank all the contributors for their excellent reviews.