Demonstrating In-Cell Target Engagement Using a Pirin Protein Degradation Probe (CCT367766)

Demonstrating
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 noncatalytic proteins, as robust proximal biomarkers
are rarely known. To confirm that our recently discovered chemical
probe 1 (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 16 (CCT367766)
in only three iterations, validating our efficient strategy for degradation
probe design against nonvalidated protein targets.