Objective

Confirming intracellular protein target engagement is an essential step in the development and progression of new chemical probes and potential small molecule therapeutics. However, this can be particularly challenging for poorly studied and non-catalytic proteins, as robust proximal biomarkers are rarely known or validated. To confirm that our recently discovered chemical probe (CCT251236) binds the putative transcription factor regulator pirin in living cells, we developed a heterobifunctional protein degradation probe. Focusing on linker design and physicochemical properties, we generated a highly active probe (CCT367766) in only three iterations, demonstrating our efficient strategy for degradation probe design against non-validated protein targets.