title: Perspectives in the development of hybrid bifunctional antitumour agents.
abstract: In spite of the development of a large number of novel target-specific antitumour agents, the single-agent therapy is in general not able to provide an effective durable control of the malignant process. The limited efficacy of the available agents (both conventional cytotoxic and novel target-specific) reflects not only the expression of defence mechanisms, but also the complexity of tumour cell alterations and the redundancy of survival pathways, thus resulting in tumour cell ability to survive under stress conditions. A well-established strategy to improve the efficacy of antitumour therapy is the rational design of drug combinations aimed at achieving synergistic effects and overcoming drug resistance. An alternative strategy could be the use of agents designed to inhibit simultaneously multiple cellular targets relevant to tumour growth/survival. Among these novel agents are hybrid bifunctional drugs, i.e. compounds resulting by conjugation of different drugs or containing the pharmocophores of different drugs. This strategy has been pursued using various conventional or target-specific agents (with DNA damaging agents and histone deacetylase inhibitors as the most exploited compounds). A critical overview of the most representative compounds is provided with emphasis on the HDAC inhibitor-based hybrid agents. In spite of some promising results, the actual pharmacological advantages of the hybrid agents remain to be defined. This commentary summarizes the recent advances in this field and highlights the pharmacological basis for a rational design of hybrid bifunctional agents.
authors.affiliation: Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milan, via Celoria 2, 20133 Milan, Italy.
authors.forename: Loana
authors.initials: L
authors.lastname: Musso
authors.affiliation: Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milan, via Celoria 2, 20133 Milan, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dallavalle
authors.affiliation: Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. Electronic address: francofzunino@gmail.com.
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D058990:Molecular Targeted Therapy; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D059003:Topoisomerase Inhibitors; D051020:bcl-X Protein
keywords: Bifunctional antitumor agents; Drugs design; Dual action; Hybrids; Multitarget compounds