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Demonstrating In-Cell Target Engagement Using a Pirin Protein Degradation Probe (CCT367766)
Nicola E A Chessum1, Swee Y Sharp1, John J Caldwell1
1Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
Journal of Medicinal Chemistry
|December 15, 2017
Summary
Researchers developed a novel protein degradation probe to confirm chemical probe 1 binds pirin in cells. This efficient strategy aids in designing probes for poorly studied, noncatalytic protein targets.
Area of Science:
- Chemical biology
- Drug discovery
- Molecular pharmacology
Background:
- Intracellular protein target engagement is crucial for developing chemical probes and therapeutics.
- Assessing engagement is difficult for noncatalytic proteins lacking known biomarkers.
Purpose of the Study:
- To confirm chemical probe 1 (CCT251236) binds the pirin protein in living cells.
- To develop an efficient strategy for designing heterobifunctional protein degradation probes against nonvalidated targets.
Main Methods:
- Designed and synthesized heterobifunctional protein degradation probes.
- Optimized linker design and evaluated physicochemical properties.
- Iteratively refined probe structures to enhance activity.
Main Results:
- Generated a highly active degradation probe, probe 16 (CCT367766), within three design iterations.
- Successfully validated the probe's ability to target pirin.
- Demonstrated an efficient approach for degradation probe development.
Conclusions:
- The developed heterobifunctional probe effectively confirms pirin engagement by chemical probe 1.
- This strategy enables the development of chemical probes for challenging, noncatalytic protein targets.
- Efficient probe design is achievable even for targets with unknown proximal biomarkers.
