Project Background
A biotech client was interested in testing whether a known BRD4 degrader scaffold could be converted into a hepatocyte-directed research tool through GalNAc conjugation. The main challenge was that the unconjugated degrader showed acceptable biochemical activity but inconsistent cellular performance in liver-relevant systems. The client needed a structured strategy to compare GalNAc presentation modes, release concepts, and degradation outcomes in ASGPR-positive cells.
Our Support
We began with a modular design campaign that compared 3 GalNAc display patterns, 2 release strategies, and multiple conjugation sites on the degrader scaffold. Structure-guided review and physicochemical filtering were used to prioritize 18 candidates for synthesis. We then evaluated receptor-dependent uptake in ASGPR-positive hepatocyte models, benchmarked target degradation in parallel ASGPR-low control cells, and analyzed intracellular BRD4 reduction by Western blot and quantitative cell assays. The final screen identified 4 conjugates with clear uptake advantages over the parent PROTAC, and 2 leads achieved more than 70% BRD4 reduction at 100 nM after 24 hours in the primary liver-relevant assay format. The best-performing design also preserved a meaningful selectivity window between ASGPR-high and ASGPR-low cells, giving the client a stronger basis for follow-up optimization.
Client Testimonial
BOC Sciences helped us convert a broad GalNAc-PROTAC idea into a disciplined experimental plan. Their team did not just synthesize molecules—they helped us understand which delivery assumptions were valid and which structural choices actually improved degradation performance in hepatocyte-relevant systems.
Project Background
A pharmaceutical research team was developing a PROTAC for a liver-associated inflammatory target, but the parent degrader showed limited performance in hepatocyte-relevant systems. The client's main goal was not simply to improve degradation potency, but to determine whether GalNAc conjugation could enhance hepatocyte-directed delivery while preserving degrader function.
Our Support
We first evaluated the target's liver relevance and the structural suitability of the client's scaffold for GalNAc conjugation. Based on this, we designed and synthesized a focused series of GalNAc-conjugated PROTAC candidates with different conjugation sites, linker properties, and cleavable elements. We then established a stepwise workflow covering ASGPR-mediated uptake, intracellular processing, and target degradation. Three candidates showed improved uptake in hepatocyte-relevant cells versus the non-GalNAc control, and one lead maintained productive degradation with more than 60% target reduction at submicromolar concentration. These results gave the client clear evidence that GalNAc conjugation was a meaningful direction for further liver-targeted optimization.
Client Testimonial
BOC Sciences helped us determine whether GalNAc conjugation could deliver a real targeting advantage in our liver-focused model. Their workflow gave us a clearer basis for next-stage design.
Enhanced Hepatocyte Targeting
