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Article: qHTSWaterfall: 3-dimensional visualization software for quantitative high-throughput screening (qHTS) data.

Queme, Bryan / Braisted, John C / Dranchak, Patricia / Inglese, James

2023 Volume 15, Issue 1, Page(s) 39

Abstract: High throughput screening (HTS) is widely used in drug discovery and chemical biology to identify and characterize agents having pharmacologic properties often by evaluation of large chemical libraries. Standard HTS data can be simply plotted as an x-y ... ...

Abstract	High throughput screening (HTS) is widely used in drug discovery and chemical biology to identify and characterize agents having pharmacologic properties often by evaluation of large chemical libraries. Standard HTS data can be simply plotted as an x-y graph usually represented as % activity of a compound tested at a single concentration vs compound ID, whereas quantitative HTS (qHTS) data incorporates a third axis represented by concentration. By virtue of the additional data points arising from the compound titration and the incorporation of logistic fit parameters that define the concentration-response curve, such as EC50 and Hill slope, qHTS data has been challenging to display on a single graph. Here we provide a flexible solution to the rapid plotting of complete qHTS data sets to produce a 3-axis plot we call qHTS Waterfall Plots. The software described here can be generally applied to any 3-axis dataset and is available as both an R package and an R shiny application.
Language	English
Publishing date	2023-03-31
Publishing country	England
Document type	Journal Article
ZDB-ID	2486539-4
ISSN	1758-2946
ISSN	1758-2946
DOI	10.1186/s13321-023-00717-9
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Article ; Online: High-Throughput Screening to Identify Inhibitors of the Type I Interferon-Major Histocompatibility Complex Class I Pathway in Skeletal Muscle.

Kinder, Travis B / Dranchak, Patricia K / Inglese, James

ACS chemical biology

2020 Volume 15, Issue 7, Page(s) 1974–1986

Abstract: Immunosuppressants used to treat autoimmunity are often not curative and have many side effects. Our purpose was to identify therapeutics for autoimmunity of the skeletal muscle termed idiopathic inflammatory myopathies (myositis). Recent evidence shows ... ...

Abstract	Immunosuppressants used to treat autoimmunity are often not curative and have many side effects. Our purpose was to identify therapeutics for autoimmunity of the skeletal muscle termed idiopathic inflammatory myopathies (myositis). Recent evidence shows that the pro-inflammatory type I interferons (IFN) and a downstream product major histocompatibility complex (MHC) class I are pathogenic in myositis. We conducted quantitative high-throughput screening on >4500 compounds, including all approved drugs, through a series of cell-based assays to identify those that inhibit the type I IFN-MHC class I pathway in muscle precursor cells (myoblasts). The primary screen utilized CRISPR/Cas9 genome-engineered human myoblasts containing a pro-luminescent reporter HiBit fused to the C-terminus of endogenous MHC class I. Active compounds were counter-screened for cytotoxicity and validated by MHC class I immunofluorescence, Western blot, and RT-qPCR. Actives included Janus kinase inhibitors, with the most potent being ruxolitinib, and epigenetic/transcriptional modulators like histone deacetylase inhibitors and the hypoxia-inducible factor 1 inhibitor echinomycin. Testing in animal models and clinical trials is necessary to translate these therapies to myositis patients. These robust assay technologies can be further utilized to interrogate the basic mechanisms of the type I IFN-MHC class I pathway, identify novel molecular probes, and elucidate possible environmental triggers that may lead to myositis.
MeSH term(s)	Cell Line ; HLA-B Antigens/drug effects ; HLA-B Antigens/metabolism ; High-Throughput Screening Assays ; Humans ; Immunologic Factors/pharmacology ; Interferon Type I/drug effects ; Interferon Type I/metabolism ; Myoblasts/drug effects ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology ; STAT1 Transcription Factor/metabolism ; Small Molecule Libraries/pharmacology
Chemical Substances	HLA-B Antigens ; Immunologic Factors ; Interferon Type I ; Protein Kinase Inhibitors ; STAT1 Transcription Factor ; STAT1 protein, human ; Small Molecule Libraries
Language	English
Publishing date	2020-06-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.0c00343
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Article ; Online: In vivo quantitative high-throughput screening for drug discovery and comparative toxicology.

Dranchak, Patricia K / Oliphant, Erin / Queme, Bryan / Lamy, Laurence / Wang, Yuhong / Huang, Ruili / Xia, Menghang / Tao, Dingyin / Inglese, James

Disease models & mechanisms

2023 Volume 16, Issue 3

Abstract: Quantitative high-throughput screening (qHTS) pharmacologically evaluates chemical libraries for therapeutic uses, toxicological risk and, increasingly, for academic probe discovery. Phenotypic high-throughput screening assays interrogate molecular ... ...

Abstract	Quantitative high-throughput screening (qHTS) pharmacologically evaluates chemical libraries for therapeutic uses, toxicological risk and, increasingly, for academic probe discovery. Phenotypic high-throughput screening assays interrogate molecular pathways, often relying on cell culture systems, historically less focused on multicellular organisms. Caenorhabditis elegans has served as a eukaryotic model organism for human biology by virtue of genetic conservation and experimental tractability. Here, a paradigm enabling C. elegans qHTS using 384-well microtiter plate laser-scanning cytometry is described, in which GFP-expressing organisms revealing phenotype-modifying structure-activity relationships guide subsequent life-stage and proteomic analyses, and Escherichia coli bacterial ghosts, a non-replicating nutrient source, allow compound exposures over two life cycles, mitigating bacterial overgrowth complications. We demonstrate the method with libraries of anti-infective agents, or substances of toxicological concern. Each was tested in seven-point titration to assess the feasibility of nematode-based in vivo qHTS, and examples of follow-up strategies were provided to study organism-based chemotype selectivity and subsequent network perturbations with a physiological impact. We anticipate that this qHTS approach will enable analysis of C. elegans orthologous phenotypes of human pathologies to facilitate drug library profiling for a range of therapeutic indications.
MeSH term(s)	Animals ; Humans ; High-Throughput Screening Assays/methods ; Caenorhabditis elegans/genetics ; Proteomics ; Drug Discovery/methods ; Small Molecule Libraries/pharmacology
Chemical Substances	Small Molecule Libraries
Language	English
Publishing date	2023-03-20
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Intramural
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.049863
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Article ; Online: High-throughput screening identifies cell cycle-associated signaling cascades that regulate a multienzyme glucosome assembly in human cells.

Schmitt, Danielle L / Dranchak, Patricia / Parajuli, Prakash / Blivis, Dvir / Voss, Ty / Kohnhorst, Casey L / Kyoung, Minjoung / Inglese, James / An, Songon

PloS one

2023 Volume 18, Issue 8, Page(s) e0289707

Abstract: We have previously demonstrated that human liver-type phosphofructokinase 1 (PFK1) recruits other rate-determining enzymes in glucose metabolism to organize multienzyme metabolic assemblies, termed glucosomes, in human cells. However, it has remained ... ...

Abstract	We have previously demonstrated that human liver-type phosphofructokinase 1 (PFK1) recruits other rate-determining enzymes in glucose metabolism to organize multienzyme metabolic assemblies, termed glucosomes, in human cells. However, it has remained largely elusive how glucosomes are reversibly assembled and disassembled to functionally regulate glucose metabolism and thus contribute to human cell biology. We developed a high-content quantitative high-throughput screening (qHTS) assay to identify regulatory mechanisms that control PFK1-mediated glucosome assemblies from stably transfected HeLa Tet-On cells. Initial qHTS with a library of pharmacologically active compounds directed following efforts to kinase-inhibitor enriched collections. Consequently, three compounds that were known to inhibit cyclin-dependent kinase 2, ribosomal protein S6 kinase and Aurora kinase A, respectively, were identified and further validated under high-resolution fluorescence single-cell microscopy. Subsequent knockdown studies using small-hairpin RNAs further confirmed an active role of Aurora kinase A on the formation of PFK1 assemblies in HeLa cells. Importantly, all the identified protein kinases here have been investigated as key signaling nodes of one specific cascade that controls cell cycle progression in human cells. Collectively, our qHTS approaches unravel a cell cycle-associated signaling network that regulates the formation of PFK1-mediated glucosome assembly in human cells.
MeSH term(s)	Humans ; HeLa Cells ; Aurora Kinase A ; High-Throughput Screening Assays ; Cell Cycle ; Glucose/metabolism
Chemical Substances	Aurora Kinase A (EC 2.7.11.1) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2023-08-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural ; Research Support, N.I.H., Extramural
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0289707
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Article ; Online: Paracatalytic induction: Subverting specificity in hedgehog protein autoprocessing with small molecules.

Ciulla, Daniel A / Xu, Zihan / Pezzullo, John L / Dranchak, Patricia / Wang, Chunyu / Giner, José-Luis / Inglese, James / Callahan, Brian P

Methods in enzymology

2023 Volume 685, Page(s) 1–41

Abstract: Paracatalytic inducers are antagonists that shift the specificity of biological catalysts, resulting in non-native transformations. In this Chapter we describe methods to discover paracatalytic inducers of Hedgehog (Hh) protein autoprocessing. Native ... ...

Abstract	Paracatalytic inducers are antagonists that shift the specificity of biological catalysts, resulting in non-native transformations. In this Chapter we describe methods to discover paracatalytic inducers of Hedgehog (Hh) protein autoprocessing. Native autoprocessing uses cholesterol as a substrate nucleophile to assist in cleaving an internal peptide bond within a precursor form of Hh. This unusual reaction is brought about by HhC, an enzymatic domain that resides within the C-terminal region of Hh precursor proteins. Recently, we reported paracatalytic inducers as a novel class of Hh autoprocessing antagonists. These small molecules bind HhC and tilt the substrate specificity away from cholesterol in favor of solvent water. The resulting cholesterol-independent autoproteolysis of the Hh precursor generates a non-native Hh side product with substantially reduced biological signaling activity. Protocols are provided for in vitro FRET-based and in-cell bioluminescence assays to discover and characterize paracatalytic inducers of Drosophila and human hedgehog protein autoprocessing, respectively.
MeSH term(s)	Animals ; Humans ; Hedgehog Proteins/genetics ; Hedgehog Proteins/chemistry ; Hedgehog Proteins/metabolism ; Drosophila Proteins/chemistry ; Drosophila/metabolism ; Cholesterol/metabolism ; Catalysis
Chemical Substances	Hedgehog Proteins ; Drosophila Proteins ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2023-04-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ISSN	1557-7988
ISSN (online)	1557-7988
DOI	10.1016/bs.mie.2023.03.001
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Article: Nonspecific membrane bilayer perturbations by ivermectin underlie SARS-CoV-2

Eastman, Richard T / Rusinova, Radda / Herold, Karl F / Huang, Xi-Ping / Dranchak, Patricia / Voss, Ty C / Rana, Sandeep / Shrimp, Jonathan H / White, Alex D / Hemmings, Hugh C / Roth, Bryan L / Inglese, James / Andersen, Olaf S / Dahlin, Jayme L

bioRxiv : the preprint server for biology

2023

Abstract: Since it was proposed as a potential host-directed antiviral agent for SARS-CoV-2, the antiparasitic drug ivermectin has been investigated thoroughly in clinical trials, which have provided insufficient support for its clinical efficacy. To examine the ... ...

Abstract	Since it was proposed as a potential host-directed antiviral agent for SARS-CoV-2, the antiparasitic drug ivermectin has been investigated thoroughly in clinical trials, which have provided insufficient support for its clinical efficacy. To examine the potential for ivermectin to be repurposed as an antiviral agent, we therefore undertook a series of preclinical studies. Consistent with early reports, ivermectin decreased SARS-CoV-2 viral burden in
Language	English
Publishing date	2023-10-24
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.23.563088
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Article ; Online: Methotrexate-based PROTACs as DHFR-specific chemical probes.

Rana, Sandeep / Dranchak, Patricia / Dahlin, Jayme L / Lamy, Laurence / Li, Wenqing / Oliphant, Erin / Shrimp, Jonathan H / Rajacharya, Girish H / Tharakan, Ravi / Holland, David O / Whitten, Apryl S / Wilson, Kelli M / Singh, Pankaj K / Durum, Scott K / Tao, Dingyin / Rai, Ganesha / Inglese, James

Cell chemical biology

2023 Volume 31, Issue 2, Page(s) 221–233.e14

Abstract: Methotrexate (MTX) is a tight-binding dihydrofolate reductase (DHFR) inhibitor, used as both an antineoplastic and immunosuppressant therapeutic. MTX, like folate undergoes folylpolyglutamate synthetase-mediated γ-glutamylation, which affects cellular ... ...

Abstract	Methotrexate (MTX) is a tight-binding dihydrofolate reductase (DHFR) inhibitor, used as both an antineoplastic and immunosuppressant therapeutic. MTX, like folate undergoes folylpolyglutamate synthetase-mediated γ-glutamylation, which affects cellular retention and target specificity. Mechanisms of MTX resistance in cancers include a decrease in MTX poly-γ-glutamylation and an upregulation of DHFR. Here, we report a series of potent MTX-based proteolysis targeting chimeras (PROTACs) to investigate DHFR degradation pharmacology and one-carbon biochemistry. These on-target, cell-active PROTACs show proteasome- and E3 ligase-dependent activity, and selective degradation of DHFR in multiple cancer cell lines. By comparison, treatment with MTX increases cellular DHFR protein expression. Importantly, these PROTACs produced distinct, less-lethal phenotypes compared to MTX. The chemical probe set described here should complement conventional DHFR inhibitors and serve as useful tools for studying one-carbon biochemistry and dissecting complex polypharmacology of MTX and related drugs. Such compounds may also serve as leads for potential autoimmune and antineoplastic therapeutics.
MeSH term(s)	Humans ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Carbon ; Folic Acid Antagonists/chemistry ; Folic Acid Antagonists/metabolism ; Folic Acid Antagonists/pharmacology ; Folic Acid Antagonists/therapeutic use ; Methotrexate/pharmacology ; Methotrexate/metabolism ; Methotrexate/therapeutic use ; Neoplasms/drug therapy ; Proteolysis Targeting Chimera ; Tetrahydrofolate Dehydrogenase/metabolism
Chemical Substances	Antineoplastic Agents ; Carbon (7440-44-0) ; Folic Acid Antagonists ; Methotrexate (YL5FZ2Y5U1) ; Proteolysis Targeting Chimera ; Tetrahydrofolate Dehydrogenase (EC 1.5.1.3)
Language	English
Publishing date	2023-10-23
Publishing country	United States
Document type	Journal Article
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2023.09.014
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Article ; Online: A cell-based bioluminescence reporter assay of human Sonic Hedgehog protein autoprocessing to identify inhibitors and activators.

Ciulla, Daniel A / Dranchak, Patricia / Pezzullo, John L / Mancusi, Rebecca A / Psaras, Alexandra Maria / Rai, Ganesha / Giner, José-Luis / Inglese, James / Callahan, Brian P

The Journal of biological chemistry

2022 , Page(s) 102705

Abstract: The Sonic hedgehog (SHh) precursor protein undergoes biosynthetic autoprocessing to cleave off and covalently attach cholesterol to the SHh signaling ligand, a vital morphogen and oncogenic effector protein. Autoprocessing is self-catalyzed by SHhC, the ... ...

Abstract	The Sonic hedgehog (SHh) precursor protein undergoes biosynthetic autoprocessing to cleave off and covalently attach cholesterol to the SHh signaling ligand, a vital morphogen and oncogenic effector protein. Autoprocessing is self-catalyzed by SHhC, the SHh precursor's C-terminal enzymatic domain. A method to screen for small molecule regulators of this process may be of therapeutic value. Here we describe the development and validation of the first cellular reporter to monitor human SHhC autoprocessing non-invasively in high-throughput compatible plates. The assay couples intracellular SHhC autoprocessing using endogenous cholesterol to the extracellular secretion of the bioluminescent nanoluciferase enzyme. We developed a wild-type (WT) SHhC reporter line for evaluating potential autoprocessing inhibitors by concentration response-dependent suppression of extracellular bioluminescence. Additionally, a conditional mutant SHhC (D46A) reporter line was developed for identifying potential autoprocessing activators by a concentration response-dependent gain of extracellular bioluminescence. The D46A mutation removes a conserved general base that is critical for the activation of the cholesterol substrate. Inducibility of the D46A reporter was established using a synthetic sterol, 2-α carboxy cholestanol, designed to bypass the defect through intra-molecular general base catalysis. To facilitate direct nanoluciferase detection in the cell culture media of 1536-well plates, we designed a novel anionic phosphonylated coelenterazine, CLZ-P, as the nanoluciferase substrate. This new reporter system offers a long-awaited resource for small molecule discovery for cancer and for developmental disorders where SHh ligand biosynthesis is dysregulated.
Language	English
Publishing date	2022-11-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2022.102705
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Article ; Online: A Macrocyclic Peptide Library with a Structurally Constrained Cyclopropane-containing Building Block Leads to Thiol-independent Inhibitors of Phosphoglycerate Mutase.

Okuma, Rika / Kuwahara, Tomoki / Yoshikane, Takafumi / Watanabe, Mizuki / Dranchak, Patricia / Inglese, James / Shuto, Satoshi / Goto, Yuki / Suga, Hiroaki

Chemistry, an Asian journal

2020 Volume 15, Issue 17, Page(s) 2631–2636

Abstract: Here we report the construction of an mRNA-encoded library of thioether-closed macrocyclic peptides by using an N-chloroacetyl-cyclopropane-containing exotic initiator whose structure is more constrained than the ordinary N-chloroacetyl-α-amino acid ... ...

Abstract	Here we report the construction of an mRNA-encoded library of thioether-closed macrocyclic peptides by using an N-chloroacetyl-cyclopropane-containing exotic initiator whose structure is more constrained than the ordinary N-chloroacetyl-α-amino acid initiators. The use of such an initiator has led to a macrocycle library with significantly suppressed population of lariat-shaped species compared with the conventional libraries. We previously used a conventional library and identified a small lariat thioether-macrocycle with a tail peptide with a C-terminal free Cys whose sidechain plays an essential role in potent inhibitory activity against a parasitic model enzyme, phosphoglycerate mutase. On the other hand, the cyclopropane-containing macrocycle library has yielded a larger thioether-macrocycle lacking a free Cys residue, which exhibits potent inhibitory activity to the same enzyme with a different mode of action. This result indicates that such a cyclopropane-containing macrocycle library would allow us to access mechanistically distinct macrocycles.
MeSH term(s)	Animals ; Caenorhabditis elegans/enzymology ; Cyclopropanes/chemistry ; Cyclopropanes/pharmacology ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Macrocyclic Compounds/chemistry ; Macrocyclic Compounds/pharmacology ; Molecular Structure ; Peptide Library ; Peptides/chemistry ; Peptides/pharmacology ; Phosphoglycerate Mutase/antagonists & inhibitors ; Phosphoglycerate Mutase/metabolism ; Sulfhydryl Compounds/chemistry ; Sulfhydryl Compounds/pharmacology
Chemical Substances	Cyclopropanes ; Enzyme Inhibitors ; Macrocyclic Compounds ; Peptide Library ; Peptides ; Sulfhydryl Compounds ; cyclopropane (99TB643425) ; Phosphoglycerate Mutase (EC 5.4.2.11)
Language	English
Publishing date	2020-08-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2233006-9
ISSN	1861-471X ; 1861-4728
ISSN (online)	1861-471X
ISSN	1861-4728
DOI	10.1002/asia.202000700
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Article ; Online: Genome-Edited Coincidence and PMP22-HiBiT Fusion Reporter Cell Lines Enable an Artifact-Suppressive Quantitative High-Throughput Screening Strategy for

Martinez, Natalia J / Braisted, John C / Dranchak, Patricia K / Moran, John J / Larson, Hunter / Queme, Bryan / Pak, Evgenia / Dutra, Amalia / Rai, Ganesha / Cheng, Ken Chih-Chien / Svaren, John / Inglese, James

ACS pharmacology & translational science

2021 Volume 4, Issue 4, Page(s) 1422–1436

Abstract: Charcot-Marie-Tooth 1A (CMT1A) is the most common form of hereditary peripheral neuropathies, characterized by genetic duplication of the critical myelin gene Peripheral Myelin Protein 22 (PMP22). ...

Abstract	Charcot-Marie-Tooth 1A (CMT1A) is the most common form of hereditary peripheral neuropathies, characterized by genetic duplication of the critical myelin gene Peripheral Myelin Protein 22 (PMP22).
Language	English
Publishing date	2021-06-10
Publishing country	United States
Document type	Journal Article
ISSN	2575-9108
ISSN (online)	2575-9108
DOI	10.1021/acsptsci.1c00110
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