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Context matters in PROTAC design: navigating the trade-off between degradation and developability
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DOI：10.1080/14756366.2026.2707656.png)
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Abstract
En 中文
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.
Keywords:
Targeted protein degradation
PROTAC
E3 ligase
ternary complex
developability
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5.4
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