2. Academic Validation
  3. Demonstrating In-Cell Target Engagement Using a Pirin Protein Degradation Probe (CCT367766)

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

  • J Med Chem. 2018 Feb 8;61(3):918-933. doi: 10.1021/acs.jmedchem.7b01406.
Nicola E A Chessum 1,  Swee Y Sharp 1,  John J Caldwell 1,  A Elisa Pasqua 1,  Birgit Wilding 1,  Giampiero Colombano 1,  Ian Collins 1,  Bugra Ozer 1,  Meirion Richards 1,  Martin Rowlands 1,  Mark Stubbs 1,  Rosemary Burke 1,  P Craig McAndrew 1,  Paul A Clarke 1,  Paul Workman 1,  Matthew D Cheeseman 1,  Keith Jones 1
Affiliations

Affiliation

  • 1 Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
PMID: 29240418 DOI: 10.1021/acs.jmedchem.7b01406
Abstract

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.

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