Project Background
A biotechnology client was interested in a transcription-regulating nuclear protein that had compelling pathway biology but lacked a validated small-molecule binder suitable for direct PROTAC design. The team needed to know whether rapid, inducible degradation of the target would produce a meaningful phenotype before allocating substantial chemistry resources.
Our Support
We first reviewed the target's domain architecture and recommended a C-terminal HaloTag fusion strategy to preserve the DNA-binding region and reduce the risk of function-disruptive tagging. We then established a cell-based degradation workflow and evaluated a focused panel of 12 HaloPROTAC-related experimental conditions, including different treatment windows, cell densities, and mechanistic control settings. After the initial screen, we identified a degradation window that produced greater than 85% target reduction within 6 hours while maintaining a clean downstream transcriptional readout. Follow-up rescue and recovery studies confirmed that the phenotype tracked with acute target loss rather than general cytotoxicity. This allowed the client to move forward with much stronger confidence in the target's degradation-dependent biology.
Client Outcome
The project delivered a reproducible HaloPROTAC validation package, a workable tagged-cell strategy, and a clear go decision for next-stage degrader discovery.
Project Background
An innovative neuroscience-focused company wanted to determine whether acute reduction of a synaptic scaffold protein would affect pathological signaling in a human iPSC-derived neuronal cell model. Because conventional inhibition was not informative and direct warhead options were limited, the client chose HaloPROTAC as a faster experimental route.
Our Support
We worked with the client to define the most relevant disease hypothesis and designed a phased study covering tagging strategy, degradation profiling, and phenotype linkage. Two fusion orientations and three assay formats were compared in parallel to identify the format that best preserved baseline biology while remaining degradation-sensitive. We then conducted dose-response and time-course studies and analyzed phenotypic endpoints alongside degradation data. Across 18 tested conditions, one optimized workflow consistently achieved deep target depletion and produced a strong shift in the client's signaling biomarker panel. The data also revealed that one construct orientation generated misleading baseline behavior, allowing the team to avoid a false-positive interpretation early in the program.
Client Outcome
The client received an optimized HaloPROTAC assay package, a prioritized construct format, and a data-backed rationale for advancing the target into a broader protein degradation campaign.
Faster Functional Validation
