Expanding Chemical Probe Space: Quality Criteria for Covalent and Degrader Probes.
Date
2023-07-27ICR Author
Author
Hartung, IV
Rudolph, J
Mader, MM
Mulder, MPC
Workman, P
Type
Journal Article
Metadata
Show full item recordAbstract
Within druggable target space, new small-molecule modalities, particularly covalent inhibitors and targeted degraders, have expanded the repertoire of medicinal chemists. Molecules with such modes of action have a large potential not only as drugs but also as chemical probes. Criteria have previously been established to describe the potency, selectivity, and properties of small-molecule probes that are qualified to enable the interrogation and validation of drug targets. These definitions have been tailored to reversibly acting modulators but fall short in their applicability to other modalities. While initial guidelines have been proposed, we delineate here a full set of criteria for the characterization of covalent, irreversible inhibitors as well as heterobifunctional degraders ("proteolysis-targeting chimeras", or PROTACs) and molecular glue degraders. We propose modified potency and selectivity criteria compared to those for reversible inhibitors. We discuss their relevance and highlight examples of suitable probe and pathfinder compounds.
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Subject
Proteolysis
Ubiquitin-Protein Ligases
Research team
Signal Trans & Mol Pharma
Language
eng
Date accepted
2023-07-05
License start date
2023-07-27
Citation
Journal of Medicinal Chemistry, 2023, 66 (14), pp. 9297 - 9312
Publisher
AMER CHEMICAL SOC