Dual PROTACs Versus Dual Inhibitors in Oncology: A Medicinal Chemistry and Linker Design Perspective

Background/Objectives: Cancer resistance, pathway redundancy, and compensatory signaling challenge traditional therapies. Dual target strategies address this by engaging two disease-relevant proteins within a single molecule. This review compares classical dual inhibitors with dual proteolysis-targeting chimeras (dual PROTACs) to evaluate the therapeutic advantages of degradation over occupancy. Methods: We examine oncology target pairs featuring documented examples of both dual inhibitors and dual PROTACs. The biological rationale for co-targeting is analyzed alongside a comparative assessment of their chemical frameworks, focusing heavily on the synthetic strategies, length, and structure of linkers required for dual PROTAC ternary complex formation. Results: While dual inhibitors rely on active-site occupancy, dual PROTACs leverage the ubiquitin-proteasome system for catalytic target elimination. Transitioning from dual inhibition to dual degradation in most cases (>85%) enhances antitumor efficacy, extends duration of action, and overcomes resistance mutations. Optimizing linker design remains the critical factor in balancing the simultaneous degradation kinetics of two distinct proteins. Conclusions: Dual PROTACs provide distinct advantages over traditional inhibitors by completely destroying target proteins rather than merely blocking them. This comparison offers a practical entry point and actionable synthetic strategies for medicinal chemists designing multi-target protein degraders.