Details

Autor(en) / Beteiligte

• Hartung, Ingo V.
• Rudolph, Joachim
• Mader, Mary M.
• Mulder, Monique P. C.
• Workman, Paul

Titel

Expanding Chemical Probe Space: Quality Criteria for Covalent and Degrader Probes

Ist Teil von

• Journal of medicinal chemistry, 2023-07, Vol.66 (14), p.9297-9312

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.