Fragment-Sized Thiazoles in Fragment-Based Drug Discovery Campaigns: Friend or Foe?

Abstract

Thiazoles exhibit a wide range of biological activities and therefore represent useful and attractive building blocks. To evaluate their usefulness and pinpoint their liabilities in fragment screening campaigns, we assembled a focused library of 49 fragment-sized thiazoles and thiadiazoles with various substituents, namely amines, bromides, carboxylic acids, and nitriles. The library was profiled in a cascade of biochemical inhibition assays, redox activity, thiol reactivity, and stability assays. Our study indicates that when thiazole derivatives are identified as screening hits, their reactivity should be carefully addressed and correlated with specific on-target engagement. Importantly, nonspecific inhibition should be excluded using experimental approaches and in silico predictions. To help with validation of hits identified in fragment screening campaigns, we can apply our highthroughput profiling workflow to focus on the most tractable compounds with a clear mechanism of action.

Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs

“…None of the compounds were redox-active, and only 22 was unstable at pH above 8.0, as our high-throughput plate reader assay determined. 48,55 However, refinement of the stability assessment by using an HPLC-based method and extending the treatment to 24 h at a pH of 7.4 revealed that most binders, with the exception of Next, effects on the crucial CRBN neosubstrates were evaluated in cellular models (Figure S5). Table 3 In previous efforts (Scheme 3), linkers were attached via a reductive amination sequence.…”

“…The aqueous stability of all compounds was determined spectrophotometrically by following the changes in the absorption spectra of the compounds, as described previously. 55 Briefly, the final mixture contained: 10 mM sodium phosphate, pH 7.0, 8.0, or 9.0, and 50 μM of the tested compound. The final concentration of was 5% (V/V).…”

Fragment Screening and Fast Micromolar Detection on a Benchtop NMR Spectrometer Boosted by Photoinduced Hyperpolarization

“…We attribute the high SNE of an estimated 3200-fold for compound 24 to its 2-aminothiazole ring which is known for redox activity, which is essential to the photo-CIDNP mechanism. [36] The thiazole ring is also found in vitamin B1 (thiamine) which is a known radical scavenger. In particular, this finding indicates that ultrahigh SNE properties can be reached by exploring the chemical space.…”

Fragment‐Screening und schnelle mikromolare Detektion mit einem Benchtop‐NMR‐Spektrometer ermöglicht durch photoinduzierte Hyperpolarisation

“…Wir führen die hohe SNE von schätzungsweise 3200‐fach für Verbindung 24 auf ihren 2‐Aminothiazol‐Ring zurück, der für seine Redox‐Aktivität bekannt ist, die für den Photo‐CIDNP‐Mechanismus wesentlich ist [36] . Der Thiazolring kommt auch in Vitamin B1 (Thiamin) vor, das ein bekannter Radikalfänger ist.…”

“…Wir führen die hohe SNE von schätzungsweise 3200-fach für Verbindung 24 auf ihren 2-Aminothiazol-Ring zurück, der für seine Redox-Aktivität bekannt ist, die für den Photo-CIDNP-Mechanismus wesentlich ist. [36] Der Thiazolring kommt auch in Vitamin B1 (Thiamin) vor, das ein bekannter Radikalfänger ist. Diese Erkenntnis deutet darauf hin, dass durch die Erforschung des chemischen Raums ultrahohe SNE-Eigenschaften erreicht werden können.…”