Perspectives in the development of hybrid bifunctional antitumour agents
Loana Musso1, Sabrina Dallavalle1, Franco Zunino2
1Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milan, via Celoria 2, 20133 Milan, Italy.
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.
Insights
Single-agent cancer therapies often fail due to tumor resistance. Hybrid bifunctional drugs, combining multiple agents, show promise for improved cancer treatment by targeting multiple pathways simultaneously.
Area of Science:
- Oncology
- Pharmacology
- Drug Discovery
Background:
- Single-agent cancer therapies exhibit limited efficacy due to tumor defense mechanisms, complex alterations, and redundant survival pathways.
- Conventional cytotoxic and novel target-specific agents struggle to achieve durable control of malignant processes.
- Tumor cells can survive under stress conditions, highlighting the need for more effective therapeutic strategies.
Purpose of the Study:
- To review the development and potential of hybrid bifunctional drugs in cancer therapy.
- To explore strategies for overcoming drug resistance and enhancing antitumour efficacy.
- To provide a pharmacological basis for the rational design of novel hybrid agents.
Main Methods:
- Critical overview of representative hybrid bifunctional agents, focusing on histone deacetylase (HDAC) inhibitor-based compounds.
- Analysis of strategies involving drug combinations and simultaneous inhibition of multiple cellular targets.
- Review of recent advances in the field of hybrid antitumour agents.
Main Results:
- Hybrid bifunctional drugs, conjugating different pharmacophores, represent an alternative strategy to drug combinations.
- HDAC inhibitor-based hybrid agents are among the most exploited compounds in this approach.
- While promising results have been observed, the definitive pharmacological advantages of hybrid agents require further definition.
Conclusions:
- Hybrid bifunctional agents offer a potential strategy to improve cancer therapy by targeting multiple pathways.
- Further research is needed to fully elucidate the pharmacological benefits and optimize the design of these novel compounds.
- Rational design of hybrid agents is crucial for overcoming drug resistance and enhancing treatment efficacy.
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