Demonstrating In-Cell Target Engagement Using a Pirin Protein Degradation Probe (CCT367766).
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Authors
Chessum, NEA
Sharp, SY
Caldwell, JJ
Pasqua, AE
Wilding, B
Colombano, G
Collins, I
Ozer, B
Richards, M
Rowlands, M
Stubbs, M
Burke, R
McAndrew, PC
Clarke, PA
Workman, P
Cheeseman, MD
Jones, K
Sharp, SY
Caldwell, JJ
Pasqua, AE
Wilding, B
Colombano, G
Collins, I
Ozer, B
Richards, M
Rowlands, M
Stubbs, M
Burke, R
McAndrew, PC
Clarke, PA
Workman, P
Cheeseman, MD
Jones, K
Document Type
Journal Article
Date
2018-02-08
Date Accepted
2017-12-14
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.
Citation
Journal of medicinal chemistry, 2018, 61 (3), pp. 918 - 933
Source Title
Publisher
AMER CHEMICAL SOC
ISSN
0022-2623
eISSN
1520-4804
Collections
Research Team
Medicinal Chemistry 2
Medicinal Chemistry 3
Signal Transduction & Molecular Pharmacology
Hit Discovery & Structural Design
Medicinal Chemistry 3
Signal Transduction & Molecular Pharmacology
Hit Discovery & Structural Design