High-Throughput Mechanism of Inhibition

Davies, Gareth; Semple, Hannah; McCandless, Megan; Cairns, Jonathan; Holdgate, Geoffrey A.

doi:10.1177/2472555220983809

Cited by 4 publications

(3 citation statements)

References 17 publications

(14 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The disease-relevant substrate of HSD17B13 is unknown, but approaches for the identification of HSD17B13 inhibitors using purified enzyme and known substrates were recently published. 20 To evaluate a potential risk of substrate-biased inhibitors, 21 − 23 we tested a small subset of compounds predictive for our full-diversity library, using purified human HSD17B13 enzyme and estradiol or leukotriene B 4 (LTB 4 ) as substrate in the presence of NAD + . We obtained a strong correlation between LTB 4 and estradiol %CTL values at 10 μM compound concentration ( Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science

et al. 2023

View full text Add to dashboard Cite

Genome-wide association studies in patients revealed HSD17B13 as a potential new target for the treatment of nonalcoholic steatohepatitis (NASH) and other liver diseases. However, the physiological function and the disease-relevant substrate of HSD17B13 remain unknown. In addition, no suitable chemical probe for HSD17B13 has been published yet. Herein, we report the identification of the novel potent and selective HSD17B13 inhibitor BI-3231. Through high-throughput screening (HTS), using estradiol as substrate, compound 1 was identified and selected for subsequent optimization resulting in compound 45 (BI-3231). In addition to the characterization of compound 45 for its functional, physicochemical, and drug metabolism and pharmacokinetic (DMPK) properties, NAD + dependency was investigated. To support Open Science, the chemical HSD17B13 probe BI-3231 will be available to the scientific community for free via the opnMe platform, and thus can help to elucidate the pharmacology of HSD17B13.

show abstract

Section: Resultsmentioning

confidence: 99%

Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science

et al. 2023

View full text Add to dashboard Cite

show abstract

“…The main challenges in this process are designing molecules with high specificity and being able to act under physiologic conditions (Bhutani et al, 2021b). In this case, a large group of compounds is routinely submitted to screening assays as potential enzymatic inhibitors (Davies et al, 2021).…”

Section: Molecular Basis Of Enzyme Inhibitionmentioning

confidence: 99%

On-flow enzymatic inhibitor screening: The emerging success of liquid chromatography-based assays

et al. 2022

View full text Add to dashboard Cite

Enzymes are targets commonly explored in screening assays aiming to discover new leads in the drug development process. Among the diverse assay models to identify new enzymatic inhibitors, on-flow assays based on liquid chromatography (LC) can be highlighted. In these approaches, the ligand-enzyme interaction can be examined by monitoring the catalytic activity or the affinity/retention. Most applications use the biological target immobilized in solid supports resulting in the acquisition of an immobilized enzymatic reactor (IMER). Coupling IMERs to LC or mass spectrometry (MS) systems allows monitoring enzyme activity online and studying binding events between target and ligands. On-flow screening assays present many advantages for the hit-to-lead process, such as the possibility of system automation, reusability, and high stability. This review covers articles from the last decade that combine the use of varied immobilization methods on different solid supports and several equipment setups in on-flow systems, emphasizing the performance and capacity of recognizing and identifying biologically active compounds in various matrices.

show abstract

“…Wilson Shou et al 23 defined how proper high-throughput analysis ensured maintenance of compound integrity and determined the highest-quality molecules to be followed up for HTS. In their article, Gareth Davies et al 24 shared a high-throughput approach to decipher the mechanism of action of compounds at enzyme targets.…”

mentioning

confidence: 99%