Project Background
A biotechnology research team was developing a BTK-targeting degrader for an activated B-cell-like DLBCL model carrying an inhibitor-resistance-associated BTK mutation. The client had an ibrutinib-derived warhead and several preliminary CRBN-recruiting PROTACs, but the first compounds showed only partial BTK reduction at 24 h and high variability between two DLBCL cell lines. The client needed a clearer design strategy to improve degradation depth while avoiding nonspecific cytotoxicity.
Our Support
BOC Sciences first reviewed the warhead structure and identified two attachment positions with lower predicted interference to BTK binding. We then designed 28 BTK PROTAC analogs using CRBN and VHL recruiters with PEG, alkyl, and semi-rigid linkers ranging from 6 to 16 atoms. Initial screening in two DLBCL cell models showed that long PEG linkers improved solubility but weakened degradation, while short alkyl linkers showed stronger cellular activity but narrower assay windows. A second optimization round focused on mid-length semi-rigid linkers and reduced polar surface area. The best analog achieved stronger BTK degradation at 8–24 h, improved Dmax compared with the starting series, and clearer suppression of downstream PLCγ2 and ERK phosphorylation markers. Proteasome inhibition and E3 ligand competition confirmed that the observed BTK reduction was PROTAC mechanism-dependent.
Client Testimonial
BOC Sciences helped us move beyond trial-and-error linker changes. Their integrated design, synthesis, and degradation assay workflow allowed us to understand why our early BTK PROTACs were inconsistent and identify a more reliable chemical direction for resistant DLBCL research.
Project Background
A pharmaceutical discovery group wanted to explore a dual-function degrader strategy for MYD88-mutant lymphoma research. The goal was to degrade IRAK4 while also modulating IKZF family transcription factors through a CRBN-associated mechanism. The client had an IRAK4-binding scaffold with measurable biochemical affinity but lacked evidence that the molecule could support productive degradation in lymphoma cells.
Our Support
We built a design matrix of 24 IRAK4-directed PROTACs using different CRBN ligand orientations and linker architectures. Early compounds degraded IKZF1/IKZF3 efficiently but produced weak IRAK4 depletion, suggesting that CRBN recruitment was active but the IRAK4 ternary complex geometry was suboptimal. We then used binding and cellular degradation data to redesign the linker exit vector and prepared 14 second-round analogs with constrained heterocyclic and semi-rigid linkers. In MYD88-mutant lymphoma cells, the optimized analog series showed improved IRAK4 reduction over a 6–24 h treatment window while retaining IKZF degradation. Downstream analysis showed reduced NF-κB pathway markers and stronger apoptosis-associated signals than the original scaffold. The final report provided the client with a ranked analog table, linker SAR interpretation, and recommended structures for further lymphoma model evaluation.
Client Testimonial
The BOC Sciences team gave us a practical path to balance IRAK4 degradation and IKZF modulation. Their ability to connect ternary complex design, linker chemistry, and lymphoma cell readouts helped us quickly refine a challenging dual-function degrader concept.
Overcoming BTK Inhibitor Resistance Through Protein Degradation
