1 Introduction Successful therapeutic treatment of solid tumors has been limited during the past decade, and avail- able anticancer strategies aimed directly at killing tumor cells leave much room for improvement. The killing of tumor cells is effective only when the antitumor drug can reach tumor cells from the circulation. Due to a solid tumor’s architecture and high interstitial pressure, however, these require- ments are not always met, resulting in limited suc- cess of chemotherapeutic, immunotoxin strategies, and radiation due to the lack of radiosensitizing oxygen. Moreover, tumor cells are genetically unstable and often develop resistance to chemical agents targeted against them. Because angiogenesis is a prerequisite for the development of metastases and the outgrowth of tumors, the use of anti-angiogenic therapy has come to the forefront, first exemplified in the clinic with Avastin ® [1–4]. Regardless of the therapeutic approach or drug of choice, monotherapy usually has limited effec- tiveness in treating cancer. Moreover, standard chemotherapy and radiation therapy always raise concerns related to systemic effects and toxicity. In this regard, use of some targeted therapy in combination with radiation and chemotherapy is likely to hold the key to future successes in the clinic. This chapter focuses on the development of non-peptidic mimetics to sensitize tumors in order to reduce toxicity from chemotherapy and radiation therapy and improve outcome. There are many potential advantages that would attend such structurally simplified, smaller therapeutic agents, the most important being increased in vivo expo- sure and reduced immunogenicity, as well as ease and cost of production. 2 Designing a Non-Peptidic Mimetic The first step to design a peptidomimetic or non- peptidic mimetic is usually the analysis of the pro- tein structure of interest, either that of the target or of the ligand, or both if one is fortunate enough to have them. Normally structure analysis of the lig- and yields more useful information, as one would like to mimic the activity of the ligand, usually to design an antagonist that tends to be easier than to design an agonist. This phase of the design often leads to structural hypotheses that are tested nor- mally by producing various amino acid substituted variants of the native sequence. In the case of a native protein, site-directed mutagenesis is usually employed by expressing the variant protein using an appropriate expression system. In the case of a peptide, variants may be synthesized chemically, and amino acid residues can be substituted, most often by using alanine scanning in which native residues are substituted with alanines one at a time, and a series of such peptides is produced that basi- cally “scan” the native sequence. In either instance, variants of the native sequence are then assessed Chapter 18 Non-Peptidic Mimetics as Cancer-Sensitizing Agents Ruud P.M. Dings, Mark Klein, and Kevin H. Mayo From: Sensitization of Cancer Cells for Chemo/Immuno/Radio-therapy, 1st Edition. 305 Edited by: Benjamin Bonavida © Humana Press, Totowa, NJ