title: Prospects on strategies for therapeutically targeting oncogenic regulatory factors by small-molecule agents.
abstract: Although the Human Genome Project has raised much hope for the identification of druggable genetic targets for cancer and other diseases, this genetic target-based approach has not improved productivity in drug discovery over the traditional approach. Analyses of known human target proteins of currently marketed drugs reveal that these drugs target only a limited number of proteins as compared to the whole proteome. In contrast to genome-based targets, mechanistic targets are derived from empirical research, at cellular or molecular levels, in disease models and/or in patients, thereby enabling the exploration of a greater number of druggable targets beyond the genome and epigenome. The paradigm shift has made a tremendous headway in developing new therapeutic agents targeting different clinically relevant mechanisms/pathways in cancer cells. In this Prospects article, we provide an overview of potential drug targets related to the following four emerging areas: (1) tumor metabolism (the Warburg effect), (2) dysregulated protein turnover (E3 ubiquitin ligases), (3) protein-protein interactions, and (4) unique DNA high-order structures and protein-DNA interactions. Nonetheless, considering the genetic and phenotypic heterogeneities that characterize cancer cells, the development of drug resistance in cancer cells by adapting signaling circuitry to take advantage of redundant pathways or feedback/crosstalk systems is possible. This "phenotypic adaptation" underlies the rationale of using therapeutic combinations of these targeted agents with cytotoxic drugs.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Chou
authors.forename: Santosh B
authors.initials: SB
authors.lastname: Salunke
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D060066:Protein Interaction Maps; D054852:Small Molecule Libraries / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; D004247:DNA; D044767:Ubiquitin-Protein Ligases
keywords: DNA QUADRUPLEX; E3 LIGASES; PROTEIN-DNA INTERACTIONS; PROTEIN-PROTEIN INTERACTIONS; WARBURG EFFECT