The E3 ligase you recruit decides where a PROTAC works, what it degrades beyond the target, and whether the ternary complex ever forms. We compare recruiters head-to-head so the choice is a data-driven design decision, not a default.
Starting with CRBN or VHL is practical, but the familiar recruiter is not automatically the right recruiter for every target. If degradation is weak, inconsistent, or difficult to optimize, the bottleneck may be the ligase–target pairing rather than the warhead itself. We help distinguish a correctable design problem from a recruiter choice that should be reconsidered.
Review Your Ligase Choice →The likely problem: binary affinity does not guarantee a productive ternary geometry or accessible ubiquitination surface. We compare alternative ligases, attachment vectors, and interface hypotheses to identify combinations more likely to support target ubiquitination.
The likely problem: an otherwise attractive recruiter may be unavailable in the relevant cell population. We integrate tissue, disease, and cell-level expression evidence so the shortlist reflects where the degrader must actually work.
The likely problem: recruiter chemistry can introduce neo-substrate or pathway effects that complicate interpretation and safety. We map known liabilities, identify selectivity controls, and assess whether another ligase offers a cleaner mechanism.
The likely problem: recruiter size, polarity, attachment vectors, or synthetic constraints may restrict linker optimization and cellular exposure. We evaluate chemistry maturity together with ternary feasibility so the preferred ligase remains practical beyond the first model.
Recruited by thalidomide-derived imides (IMiDs). The most tractable and chemically mature recruiter, with rich SAR and a broad toolkit of ligands.
Recruited by hydroxyproline-based ligands. VHL offers mature, selective recruiter chemistry and generally lower known neo-substrate liability than IMiD-based CRBN recruitment, but its recruiter head is larger and more polar.
Recruited by nutlin- or spiro-oxindole-derived ligands. MDM2 can be valuable when p53-pathway biology is relevant, but its expression, pathway effects, and recruiter context require project-specific evaluation.
Recruited by AVPI-mimetic ligands. IAP-based degraders can be useful in selected disease contexts, but recruiter-induced IAP auto-degradation and pathway signaling must be measured and controlled.
Aryl sulfonamides such as indisulam recruit RBM39 to DCAF15 through a molecular-glue mechanism. DCAF15 is biologically important for targeted degradation, but its use as a general bifunctional PROTAC recruiter remains comparatively limited and should be treated as exploratory.
DCAF16 can be engaged by covalent electrophilic chemistry and has enabled degradation of nuclear proteins in experimental systems. Its recruiter reactivity, cellular localization, selectivity, and evidence depth require careful project-specific review.
Every column below is scored from available structural, chemogenomic, and expression evidence, then reconciled with the target geometry your warhead imposes.
| Ligase | Recruiter ligand | Known liability | Recruiter size | Recruiter maturity | Best-fit scenario |
|---|---|---|---|---|---|
| CRBN | IMiD / glutarimide | Chemotype-dependent neo-substrates | Small | High | Broad first-pass programs with selectivity controls |
| VHL | Hydroxyproline (VH032) | Lower known neo-substrate liability | Large / polar | High | Mature alternative when geometry and properties fit |
| MDM2 | Nutlin / spiro-oxindole | p53-pathway coupling | Medium | Medium | Programs where MDM2 and p53 biology are relevant |
| IAP | AVPI mimetic | Auto-degradation / signaling | Medium | Medium | Selected contexts with appropriate pathway controls |
| DCAF15 | Aryl sulfonamide | RBM39/RBM23 molecular-glue activity | Small | Experimental | Molecular-glue-informed exploratory programs |
| DCAF16 | Covalent electrophile | Reactivity / limited selectivity data | Small | Experimental | Nuclear-target exploratory programs |
The workflow moves from broad landscape to a scored, defensible shortlist, holding biology and chemistry in the same decision frame.
Request a Ligase AssessmentAssemble candidate ligases, their ligands, expression profiles, and neo-substrate liabilities relative to the disease tissue and target.
Evaluate available ligand chemotypes, synthetic accessibility, attachment vectors, and known SAR for each candidate recruiter.
Test whether target and ligase can form a linker-compatible, cooperative interface for each recruiter under consideration.
Combine selectivity, expression, geometry, and chemistry into a ranked recommendation with controls and validation experiments.
CRBN-based degraders can also remove IKZF1/3 or GSPT1; IAP degraders can drive self-degradation. We surface these consequences explicitly so the shortlist reflects selectivity, not just ternary formation.
Each recruiter is scored against the specific target, tissue, and warhead chemistry you bring. Outputs separate structurally supported fits from higher-risk alternatives.
Expression, neo-substrate, and ligandability profiles for every ligase considered.
Side-by-side scoring across selectivity, geometry, and chemistry criteria.
Off-target degradation risks and proposed controls for each shortlisted recruiter.
Ranked ligase shortlist, linker/vector guidance, and validation experiment plan.
A large chemistry and chemoproteomics platform mapped kinase degradation across CRBN- and VHL-recruiting compounds. The results showed that degradation depends on the combined target ligand, degrader chemistry, and recruited E3 ligase, supporting empirical and proteome-aware recruiter comparison rather than selection by precedent alone.
The authors systematically characterized E3 ligases across chemical ligandability, expression, protein interactions, structure availability, functional essentiality, cellular location, and interaction interfaces using 30 large-scale datasets. Their integrated analysis identified 76 E3 ligases as candidate partners for targeted protein degradation.
The right ligase depends on your target, tissue, and chemistry—these answers explain how we make that determination.
We compare mature recruiters such as CRBN and VHL, evaluate alternatives including MDM2 and IAP where appropriate, and review emerging ligases such as DCAF15, DCAF16, and KEAP1 on an evidence-dependent basis. Each option is profiled for expression, known liabilities, recruiter maturity, and target-specific ternary feasibility.
The choice depends on the target, the tissue of interest, the surface complementarity between the two proteins, and the attachment vectors available from each warhead. We score these factors together rather than defaulting to a single ligase.
Yes. Depending on the recruiter chemotype and cellular context, CRBN-recruiting degraders may affect neo-substrates such as IKZF1/3 or GSPT1. We flag relevant selectivity risks and propose controls or alternative ligases when they could confound interpretation.
Yes. We integrate proteomic and transcriptomic expression data to prioritize ligases expressed in the disease-relevant tissue, which helps avoid recruiting a ligase that is absent or low in the target compartment.
The target protein, the disease tissue, any known ligands or warheads, and any degradation or binding data you already have. From these we can scope a ligase comparison and a shortlist of recommended recruiters.
Share the target, tissue, and any known ligands. CD ComputaBio will scope a ligase comparison and identify the minimum additional data needed to lock in a defensible choice. Related services: E3 Ligase Ligand Design Service, PROTAC Linker Design and Optimization, PROTAC Molecular Dynamics Service.
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