ReviewJournal of enzyme inhibition and medicinal chemistry2026
Context matters in PROTAC design: navigating the trade-off between degradation and developability.
Review in Journal of enzyme inhibition and medicinal chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Proteolysis-targeting chimaeras (PROTACs) couple target recognition to ubiquitin-dependent degradation, but their translation requires coordinated optimisation of degradation efficiency and developability. This review frames PROTAC design as a context-dependent medicinal chemistry problem rather than modular assembly of a warhead, linker and ubiquitin ligase (E3) recruiter. Linker length, rigidity, and exit vectors, together with warhead recognition topology, determine whether binary binding can form a cooperative, ubiquitination-competent ternary complex. Warhead binding mode further affects catalytic turnover and cellular degradation. Linker-free designs and disclosed clinical PROTAC structures show that beyond Rule of Five property control remains central to exposure. Conditional linkers and E3 ligase choice add biological constraints through stimulus-responsive activation, recruiter tractability, E3 expression, localisation, pathway biology, and safety liabilities. This review integrates these principles into a framework for PROTAC design. The framework aligns productive ternary complex assembly, effective exposure and biological-context compatibility within the intended therapeutic context.
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