Targetome-guided combination drug discovery: A new paradigm for next‑generation therapeutics

For decades, the “one gene, one target, one drug” model has dominated drug discovery but increasingly fails to deliver sufficient efficacy for complex chronic diseases, due to pathway redundancy, compensatory feedback, target exhaustion, and high clinical attrition. Empirical combinations of marketed drugs dominate today’s combination therapies, leaving a critical gap in de novo target‑driven combinatorial drug development.

A research team led by Professor Haiping Hao (President, China Pharmaceutical University) and Professor Xiao Zheng (China Pharmaceutical University) systematically reviewed the frontier advances and proposed a unified targetome framework to guide rational, mechanism‑driven combination therapy discovery. The concept defines the full set of molecular targets (proteins, nucleic acids, etc.) that can be modulated synergistically to treat a specific disease, moving beyond empirical polypharmacy to systems‑level network pharmacology.

The authors outline a three‑stage evolution of combination drug development:

1. V1.0: Empirical combinations of marketed drugs and herbal medicines

2. V2.0: Original drugs combined with approved agents

3. V3.0: De novo discovery driven by targetome identification and phenotypic screening, hailed as next‑generation therapeutics.

The review establishes a complete innovation framework covering:

- Identification of key signaling networks and synergistic targets in complex diseases

- Systematic druggability validation of combined targets

- Rational drug design for synergistic targets using endogenous ligands, structural biology, and AI

- Diverse discovery strategies: natural products, endogenous molecules, drug repurposing, AI/big data, phenotypic screening, and host–microbiota crosstalk targeting.

Notably, the team highlights that AI and big data are transforming targetome research from static mapping to dynamic synergistic network analysis and de novo molecular design, greatly improving efficiency and success rates. Spatiotemporal signal regulation, precision target control, clinical translation, pharmacokinetics, and drug delivery are also addressed as key enablers for clinical impact.

This work provides a foundational theoretical and methodological blueprint for global researchers to develop safer, more effective multi‑target therapeutics, addressing the unmet clinical need for curative treatments of chronic diseases.

The review, entitled “Targetome‑guided combination drug discovery as next‑generation therapeutics”, was published online October 22, 2025, in Targetome.