Journal: Frontiers in Pharmacology

Article Title: Epigenetic small-molecule screen for inhibition and reversal of acinar ductal metaplasia in mouse pancreatic organoids

doi: 10.3389/fphar.2024.1335246

Figure Lengend Snippet: Schematic representation of the ADM screen. Seeded organoids originating from wildtype (WT) or p48 Cre/+ (Cre) mice were treated with the Cayman small-molecule epigenetic modulator library (ESL) at final concentration of 1 µM using an automated dispensing system and left to incubate for 72 h. Following incubation, organoids were stained using the calcein AM viability dye and imaged using a high throughput imaging system at ×20 magnification to obtain high resolution images for further image analysis.

Article Snippet: We screened the Cayman’s small-molecule epigenetic modulator library (ESL) which contains 144 compounds with the goal to identify important regulators of ADM with therapeutic potential.

Techniques: Concentration Assay, Incubation, Staining, High Throughput Screening Assay, Imaging

Journal: Frontiers in Pharmacology

Article Title: Epigenetic small-molecule screen for inhibition and reversal of acinar ductal metaplasia in mouse pancreatic organoids

doi: 10.3389/fphar.2024.1335246

Figure Lengend Snippet: ADM inhibition from epigenetic compound library screen (compounds 1–68 grouped by target). The ADM inhibition assay screen was performed in duplicate using the Cayman ESL on wildtype mouse organoids. The mean percentage of viable ducts and acinar clusters (± SD) 72 h post treatment. BET = bromodomain and extraterminal domain inhibitors; DMT = DNA methyltransferase inhibitors; HDM = histone demethylase inhibitors; HMT = histone methyltransferase inhibitors; HAT = histone acetyltransferase inhibitors; HDAC = histone deacetylase inhibitors (NAD + dependent); HCl = hydrochloride; TFA salt = trifluoroacetic acid salt. p values were calculated using two-tailed Student’s t -test with unequal variances. Significance was accepted at p ≤ 0.05 only when averages of clusters are higher than the respective vehicle control. * p -value = 0.05–0.01; ** p -value = 0.01–0.001; *** p -value < 0.001. Red asterisks denote compounds that showed significantly higher cluster/duct ratios of live objects but had overall less than 50% viability of total objects (false positive). Black asterisks denote compounds that showed significantly higher cluster/duct ratios of live objects and more than 50% of total objects were viable by calcein AM staining (true positive). Single biological replicate of quadruplicate technical replicates, mean ± SD.

Article Snippet: We screened the Cayman’s small-molecule epigenetic modulator library (ESL) which contains 144 compounds with the goal to identify important regulators of ADM with therapeutic potential.

Techniques: Inhibition, Drug discovery, Histone Deacetylase Assay, Two Tailed Test, Control, Staining

Journal: Frontiers in Pharmacology

Article Title: Epigenetic small-molecule screen for inhibition and reversal of acinar ductal metaplasia in mouse pancreatic organoids

doi: 10.3389/fphar.2024.1335246

Figure Lengend Snippet: ADM inhibition from epigenetic compound library screen (compounds 69–144 grouped by target). The ADM inhibition assay screen was performed in duplicate using the Cayman ESL on wildtype mouse organoids. The mean percentage of viable ducts and acinar clusters (± SD) 72 h post treatment. HDAC = histone deacetylase inhibitors (Zn 2+ dependent); PARP = poly-ADP ribose polymerase inhibitors; HCl = hydrochloride; TFA salt = trifluoroacetic acid salt. p values were calculated using two-tailed Student’s t-test with unequal variances. Significance was accepted at p ≤ 0.05 only when averages of clusters are higher than the respective vehicle control. * p -value = 0.05–0.01; ** p -value = 0.01–0.001; *** p -value < 0.001. Red asterisks denote compounds that showed significantly higher cluster/duct ratios of live objects but had overall less than 50% viability of total objects (false positive). Black asterisks denote compounds that showed significantly higher cluster/duct ratios of live objects and more than 50% of total objects were viable by calcein AM staining (true positive). Single biological replicate of quadruplicate technical replicates, mean ± SD.

Article Snippet: We screened the Cayman’s small-molecule epigenetic modulator library (ESL) which contains 144 compounds with the goal to identify important regulators of ADM with therapeutic potential.

Techniques: Inhibition, Drug discovery, Histone Deacetylase Assay, Two Tailed Test, Control, Staining

Journal: Frontiers in Pharmacology

Article Title: Epigenetic small-molecule screen for inhibition and reversal of acinar ductal metaplasia in mouse pancreatic organoids

doi: 10.3389/fphar.2024.1335246

Figure Lengend Snippet: ADM reversal from epigenetic compound library screen (compounds 1–68 grouped by target). The ADM reversal assay screen was performed in duplicate using the Cayman ESL on Cre mouse organoids. The mean percentage of viable ducts and acinar clusters (± SD) 72 h post treatment. BET = bromodomain and extraterminal domain inhibitors; DMT = DNA methyltransferase inhibitors; HDM = histone demethylase inhibitors; HMT = histone methyltransferase inhibitors; HAT = histone acetyltransferase inhibitors; HDAC = histone deacetylase inhibitors (NAD + dependent); HCl = hydrochloride; TFA salt = trifluoroacetic acid salt. p values were calculated using two-tailed Student’s t-test with unequal variances. Significance was accepted at p ≤ 0.05 only when averages of clusters are higher than the respective vehicle control. * p -value = 0.05–0.01; ** p -value = 0.01–0.001; *** p -value < 0.001. Black asterisks denote compounds that showed significantly higher cluster/duct ratios of live objects and more than 50% of total objects were viable by calcein AM staining (true positive). Single biological replicate of quadruplicate technical replicates, mean ± SD.

Article Snippet: We screened the Cayman’s small-molecule epigenetic modulator library (ESL) which contains 144 compounds with the goal to identify important regulators of ADM with therapeutic potential.

Techniques: Drug discovery, Histone Deacetylase Assay, Two Tailed Test, Control, Staining

Journal: Frontiers in Pharmacology

Article Title: Epigenetic small-molecule screen for inhibition and reversal of acinar ductal metaplasia in mouse pancreatic organoids

doi: 10.3389/fphar.2024.1335246

Figure Lengend Snippet: ADM reversal from epigenetic compound library screen (compounds 69–144 grouped by target). The ADM reversal assay screen was performed in duplicate using the Cayman ESL on Cre mouse organoids. The mean percentage of viable ducts and acinar clusters (± SD) 72 h post treatment. HDAC = histone deacetylase inhibitors (Zn 2+ dependent); PARP = poly-ADP ribose polymerase inhibitors; HCl = hydrochloride; TFA salt = trifluoroacetic acid salt. p values were calculated using two-tailed Student’s t-test with unequal variances. Significance was accepted at p ≤ 0.05 only when averages of clusters are higher than the respective vehicle control. * p -value = 0.05–0.01; ** p -value = 0.01–0.001; *** p -value < 0.001. Red asterisks denote compounds that showed significantly higher cluster/duct ratios of live objects but had overall less than 50% viability of total objects (false positive). Black asterisks denote compounds that showed significantly higher cluster/duct ratios of live objects and more than 50% of total objects were viable by calcein AM staining (true positive). Single biological replicate of quadruplicate technical replicates, mean ± SD.

Article Snippet: We screened the Cayman’s small-molecule epigenetic modulator library (ESL) which contains 144 compounds with the goal to identify important regulators of ADM with therapeutic potential.

Techniques: Drug discovery, Histone Deacetylase Assay, Two Tailed Test, Control, Staining

Journal: Molecules

Article Title: Virtual Screening in the Identification of Sirtuins’ Activity Modulators

doi: 10.3390/molecules27175641

Figure Lengend Snippet: Perspective of the computational studies leading to the identification of selective and/or pan-Sirtuins modulators (shown in green). The chemical structure and the explored biological activity of the discovered hit compounds are reported. The applied virtual screening (VS) strategy is specified as structure-based (SBVS) or ligand-based (LBVS) methodology. The results are listed based on the sirtuin type (alternatively in gray and cyan), according to SBVS followed by LBVS and combined SB-LB approaches, as chronological order. Data about parasitic sirtuins (depicted in coral) are also detailed, referring to the Leishmania (Lm-Sirt), Trypanosoma cruzi (Tc-Sirt) and Schistosoma mansoni (Sm-Sirt) sirtuins.

Article Snippet: 2014 , [ ] , Structure-based drug design of small molecule SIRT-1 modulators to treat cancer and metabolic disorders , 1 , SBVS , Target model for inhibitors: crystal structureTarget model for activators: HM of the allosteric site , Not tested , YES , Asinex (>600000) , Glide 5.0 , , I, A , 16.35 μM (IC 50 ).

Techniques: Activity Assay, Biomarker Discovery, Software, Inhibition, In Silico, Functional Assay, In Vitro, Sequencing, Generated, Histone Deacetylase Assay, Binding Assay, Analogues, Drug discovery, Purification, Modification, Activation Assay, Derivative Assay