Project Background
A biotech client had a hematologic malignancy target with strong disease relevance but limited success from inhibitor optimization. The team wanted to test whether a UPS-based degrader strategy could produce deeper pathway suppression than occupancy-based inhibition.
Our Support
We began with a degradability and target-accessibility assessment, then designed two bifunctional degrader series around the client's validated binding motif using alternative ligase recruitment logic. Across the first design cycle, we prepared 18 molecules with varied linker composition, attachment vectors, and ligand polarity. Ternary complex profiling and cell-based degradation studies identified one VHL-oriented series with clearly superior productivity. Follow-up optimization narrowed the set to 6 prioritized analogs, of which 2 delivered DC50 values below 100 nM in the client's lead cell model and showed more than 80% target reduction at 6 hours, while negative-control analogs did not reproduce the effect.
Project Outcome
The client obtained a credible UPS-mediated degrader series, a cleaner mechanism package linking ligase recruitment to target loss, and a more focused medicinal chemistry direction for subsequent optimization.
Project Background
A discovery-stage partner was exploring an immunology target for which bifunctional degrader architecture appeared chemically challenging. The client wanted a structured way to evaluate whether a molecular-glue-like UPS approach could be feasible, but lacked an internal workflow for ligase dependency testing, ubiquitination readouts, and orthogonal mechanism confirmation.
Our Support
We designed a staged mechanism-first program combining target biology review, ligase shortlist generation, biochemical interaction studies, ubiquitination readouts, and cellular protein reduction assays. We screened 24 focused compounds and analogs across a tiered cascade that included ligase activity testing, ubiquitination signal tracking, proteasome-dependency confirmation, and target-selective immunoblot analysis. Three compounds showed reproducible target reduction, and one chemotype produced a consistent UPS-linked signature with proteasome rescue, measurable ubiquitination enhancement, and limited impact on related pathway proteins under the same conditions.
Project Outcome
The partner received a practical feasibility conclusion, a prioritized chemotype for expansion, and an assay workflow that could be reused for future UPS-based discovery efforts on the same target family.
Removes the Target Protein Itself
