Targetome-guided combination drug discovery as next-generation therapeutics

Abstract

The limited efficacy of 'one gene, one target' drugs for major chronic diseases such as cancer and cardiovascular disease has spurred the clinical development of combination therapies, with the hope of attaining synergistic activity and/or overcoming treatment resistance. This paradigm shift is witnessed against the accumulation of insights into the inherent complexity of biological systems and chronic diseases, which serves as the basic logic for the quest for drug combinations. Several combinatorial agents have been approved by the FDA, and many candidates are currently under clinical trial. However, the design of these drugs has been mostly restricted to the empirical combination of marketed drugs. Given the limited target landscape in the current drug development pipeline, there is an unmet need to identify innovative combination drugs based on de novo targetome discovery. In this review, major progress in this frontier is synthesized and three potential routes are proposed that could be pursued for the discovery of next-generation combination drugs. Key dimensions for targetome identification and validation are considered, based on the signaling network of chronic diseases and regulatory principles of targets. Opportunities for harnessing the technical advances in disease biology and drug design to overcome challenges associated with these combinatorial strategies are discussed.

Keywords

Drug discovery / Combination drug / Targetome / Chronic diseases / Target identification

Ethical statements

Not applicable.

Author contributions

The authors confirm their contributions to the paper as follows: conceptualization: Hao H, Zheng X; writing of this manuscript: Hao H, Liu P, Huang F; revision of this manuscript: Zheng X, Liu P, Huang F. All authors reviewed the results and approved the final version of the manuscript.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Acknowledgments

This work was supported by the National Key Research and Development Program of China (grant 2021YFA1301300 to H.H.), and the Natural Science Foundation of Jiangsu Province (grant BK20240095 to X.Z.).

Conflict of interest

The authors declare that they have no conflict of interest.

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