Project Background
A biotechnology client had a validated covalent BTK-binding scaffold and wanted to convert it into a degrader series with stronger pathway suppression in cellular models. The main challenge was that direct conversion of the covalent inhibitor into bifunctional molecules risked losing degradation productivity because of steric constraints, linker mismatch, and uncertainty around whether irreversible target engagement would still support efficient protein turnover.
Our Support
We first reviewed the binding mode of the client's scaffold and mapped feasible derivatization positions that would preserve covalent engagement while leaving room for degrader assembly. We then designed 24 covalent PROTAC candidates across two warhead presentation strategies, three linker classes, and both CRBN- and VHL-oriented E3 recruitment options. After synthesis, we performed binding analysis, ternary complex assessment, and cellular degradation studies. Early data showed that several high-reactivity molecules bound well but degraded poorly, so the project was redirected toward lower-burden linker designs and a more geometry-driven series. This optimization step produced 3 molecules with clear BTK degradation, including 1 lead that achieved sub-100 nM DC50, improved pathway suppression relative to the parent inhibitor, and a cleaner dose-response profile in the client's preferred cell system.
Client Testimonial
BOC Sciences helped us move beyond a simple inhibitor-to-PROTAC conversion mindset. Their team quickly identified why our first design assumptions were not producing productive degradation and then built a more effective optimization path supported by solid chemistry and biology data.
Project Background
A drug discovery company was pursuing an oncology target with a mutant-associated cysteine located near a ligandable pocket. The client wanted a covalent PROTAC strategy that could improve mutant preference while maintaining strong degradation activity, but lacked a clear framework for choosing warhead type, attachment position, and degrader architecture.
Our Support
We began with target structure analysis, ligand review, and residue accessibility assessment, then compared irreversible and reversible covalent concepts for the program's biology goals. Based on these findings, we designed 18 first-round molecules and used a staged screen to evaluate binding behavior, degradation trend, mutant-to-wild-type selectivity, and physicochemical properties. Several early irreversible designs showed acceptable target engagement but limited degradation efficiency, suggesting that warhead placement was impairing ternary complex formation. We therefore shifted the chemistry strategy toward a revised exit vector and a less conformationally restrictive linker series. In the second round, 2 candidates demonstrated strong degradation of the mutant-associated target form, measurable selectivity over the reference protein background, and improved solubility and microsomal stability compared with the initial set. These results gave the client a prioritized series for continued lead optimization.
Client Testimonial
The BOC Sciences team brought real problem-solving value to our project. They did not just synthesize molecules; they helped us understand which structural choices were helping or hurting covalent degradation and delivered a much clearer path for the next stage.
Expands Access to Difficult Binding Opportunities
