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Book ; Online: Special Topics in Drug Discovery

Chen, Taosheng / Chai, Sergio C

2016

Keywords	Pharmacology ; biotechnology, screening, toxicology, inhibitors, surface plasmon resonance, matrix
Language	English
Size	1 electronic resource (190 pages)
Publisher	IntechOpen
Document type	Book ; Online
Note	English
HBZ-ID	HT030645856
ISBN	9789535173250 ; 9535173251
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article ; Online: Regulation of PXR in drug metabolism: chemical and structural perspectives.

Gee, Rebecca R Florke / Huber, Andrew D / Chen, Taosheng

Expert opinion on drug metabolism & toxicology

2024 Volume 20, Issue 1-2, Page(s) 9–23

Abstract: Introduction: Pregnane X receptor (PXR) is a master xenobiotic sensor that transcriptionally controls drug metabolism and disposition pathways. PXR activation by pharmaceutical drugs, natural products, environmental toxins, etc. may decrease drug ... ...

Abstract	Introduction: Pregnane X receptor (PXR) is a master xenobiotic sensor that transcriptionally controls drug metabolism and disposition pathways. PXR activation by pharmaceutical drugs, natural products, environmental toxins, etc. may decrease drug efficacy and increase drug-drug interactions and drug toxicity, indicating a therapeutic value for PXR antagonists. However, PXR's functions in physiological events, such as intestinal inflammation, indicate that PXR activators may be useful in certain disease contexts. Areas covered: We review the reported roles of PXR in various physiological and pathological processes including drug metabolism, cancer, inflammation, energy metabolism, and endobiotic homeostasis. We then highlight specific cellular and chemical routes that modulate PXR activity and discuss the functional consequences. Databases searched and inclusive dates: PubMed, 1 January 1980 to 10 January 2024. Expert opinion: Knowledge of PXR's drug metabolism function has helped drug developers produce small molecules without PXR-mediated metabolic liabilities, and further understanding of PXR's cellular functions may offer drug development opportunities in multiple disease settings.
MeSH term(s)	Humans ; Pregnane X Receptor/metabolism ; Receptors, Steroid/metabolism ; Inactivation, Metabolic ; Inflammation
Chemical Substances	Pregnane X Receptor ; Receptors, Steroid
Language	English
Publishing date	2024-01-28
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2214462-6
ISSN	1744-7607 ; 1742-5255
ISSN (online)	1744-7607
ISSN	1742-5255
DOI	10.1080/17425255.2024.2309212
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Article ; Online: General Stepwise Approach to Optimize a TR-FRET Assay for Characterizing the BRD/PROTAC/CRBN Ternary Complex.

Lin, Wenwei / Chen, Taosheng

ACS pharmacology & translational science

2021 Volume 4, Issue 2, Page(s) 941–952

Abstract: Proteolysis-targeting chimeras (PROTACs) degrade target proteins by engaging the ubiquitin-proteasome system. Assays detecting target-PROTAC-E3 ligase ternary complexes are critical for PROTAC development. Both time-resolved fluorescence energy transfer ( ...

Abstract	Proteolysis-targeting chimeras (PROTACs) degrade target proteins by engaging the ubiquitin-proteasome system. Assays detecting target-PROTAC-E3 ligase ternary complexes are critical for PROTAC development. Both time-resolved fluorescence energy transfer (TR-FRET) assays and amplified luminescent proximity homogeneous assays can characterize ternary complexes and assess PROTAC efficacy; stepwise optimization protocols for these assays are lacking. To identify assay conditions that can be applied to various targets and PROTACs, we used a stepwise approach to optimize a TR-FRET assay of BRD2(BD1)/PROTACs/CRBN ternary complexes. This assay is sensitive and specific and responds to the bivalent PROTACs dBET1, PROTAC BET Degrader-1, and PROTAC BET Degrader-2 but not to non-PROTAC ligands of BRD2(BD1) or CRBN. The activity rank order of dBET1, PROTAC BET Degrader-1, and PROTAC BET Degrader-2 in the TR-FRET assay corresponded with previously reported cell growth inhibition assays, indicating the effectiveness of our assay for predicting PROTAC cellular activity. The TR-FRET ternary complex formation assay for BRD2(BD1)/PROTAC/CRBN can be configured to characterize the binding activities of BRD2(BD1) and CRBN ligands with the same compound activity rank order as that of previously reported binary binding assays for individual targets but with the advantage of simultaneously assessing the ligand activities for both targets. Our assay is modular in nature, as BRD2(BD1) can be replaced with other BRDs and successfully detect ternary complexes without modifying other assay conditions. Therefore, the TR-FRET ternary complex assay for BRDs provides a general assay protocol for establishing assays for other targets and bivalent molecules.
Language	English
Publishing date	2021-02-26
Publishing country	United States
Document type	Journal Article
ISSN	2575-9108
ISSN (online)	2575-9108
DOI	10.1021/acsptsci.1c00032
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Regulation of Nuclear Receptors PXR and CAR by Small Molecules and Signal Crosstalk: Roles in Drug Metabolism and Beyond.

Poudel, Shyaron / Huber, Andrew D / Chen, Taosheng

Drug metabolism and disposition: the biological fate of chemicals

2022 Volume 51, Issue 2, Page(s) 228–236

Abstract: Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are ligand-activated transcription factors that regulate the expression of drug metabolizing enzymes and drug transporters. Since their discoveries, they have been studied as important ... ...

Abstract	Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are ligand-activated transcription factors that regulate the expression of drug metabolizing enzymes and drug transporters. Since their discoveries, they have been studied as important factors for regulating processes related to drug efficacy, drug toxicity, and drug-drug interactions. However, their vast ligand-binding profiles extend into additional spaces, such as endogenously produced chemicals, microbiome metabolites, dietary compounds, and environmental pollutants. Therefore, PXR and CAR can respond to an enormous abundance of stimuli, resulting in significant shifts in metabolic programs and physiologic homeostasis. Naturally, PXR and CAR have been implicated in various diseases related to homeostatic perturbations, such as inflammatory bowel disorders, diabetes, and certain cancers. Recent findings have injected the field with new signaling mechanisms and tools to dissect the complex PXR and CAR biology and have strengthened the potential for future PXR and CAR modulators in the clinic. Here, we describe the historical and ongoing importance of PXR and CAR in drug metabolism pathways and how this history has evolved into new mechanisms that regulate and are regulated by these xenobiotic receptors, with a specific focus on small molecule ligands. To effectively convey the impact of newly emerging research, we have arranged five diverse and representative key recent advances, four specific challenges, and four perspectives on future directions. SIGNIFICANCE STATEMENT: PXR and CAR are key transcription factors that regulate homeostatic detoxification of the liver and intestines. Diverse chemicals bind to these nuclear receptors, triggering their transcriptional tuning of the cellular metabolic response. This minireview revisits the importance of PXR and CAR in pharmaceutical drug responses and highlights recent results with implications beyond drug metabolism.
MeSH term(s)	Constitutive Androstane Receptor ; Pregnane X Receptor ; Receptors, Steroid/metabolism ; Ligands ; Receptors, Cytoplasmic and Nuclear ; Xenobiotics/metabolism
Chemical Substances	Constitutive Androstane Receptor ; Pregnane X Receptor ; Receptors, Steroid ; Ligands ; Receptors, Cytoplasmic and Nuclear ; Xenobiotics
Language	English
Publishing date	2022-09-18
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.122.000858
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Article ; Online: Discovering Anti-cancer Immune Enhancers in a Miniaturized Immune-Tumor Microenvironment.

Huber, Andrew D / Chen, Taosheng

Cell chemical biology

2019 Volume 26, Issue 3, Page(s) 314–316

Abstract: In this issue of Cell Chemical Biology, Mo et al. (2019) report the development and validation of a co-culture system with cancer and immune cells that is suitable for high-throughput screening. The method is an important step forward in technologies for ...

Abstract	In this issue of Cell Chemical Biology, Mo et al. (2019) report the development and validation of a co-culture system with cancer and immune cells that is suitable for high-throughput screening. The method is an important step forward in technologies for identifying cancer-cell-specific immunotherapies.
MeSH term(s)	Early Detection of Cancer ; Humans ; Immunologic Factors ; Immunotherapy ; Neoplasms ; Tumor Microenvironment
Chemical Substances	Immunologic Factors
Language	English
Publishing date	2019-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2019.03.004
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Article ; Online: A high-content screen of FDA approved drugs to enhance CAR T cell function: ingenol-3-angelate improves B7-H3-CAR T cell activity by upregulating B7-H3 on the target cell surface via PKCα activation.

Lee, Ha Won / O'Reilly, Carla / Beckett, Alex N / Currier, Duane G / Chen, Taosheng / DeRenzo, Christopher

Journal of experimental & clinical cancer research : CR

2024 Volume 43, Issue 1, Page(s) 97

Abstract: Background: CAR T cell therapy is a promising approach to improve outcomes and decrease toxicities for patients with cancer. While extraordinary success has been achieved using CAR T cells to treat patients with CD19-positive malignancies, multiple ... ...

Abstract	Background: CAR T cell therapy is a promising approach to improve outcomes and decrease toxicities for patients with cancer. While extraordinary success has been achieved using CAR T cells to treat patients with CD19-positive malignancies, multiple obstacles have so far limited the benefit of CAR T cell therapy for patients with solid tumors. Novel manufacturing and engineering approaches show great promise to enhance CAR T cell function against solid tumors. However, similar to single agent chemotherapy approaches, CAR T cell monotherapy may be unable to achieve high cure rates for patients with difficult to treat solid tumors. Thus, combinatorial drug plus CAR T cell approaches are likely required to achieve widespread clinical success. Methods: We developed a novel, confocal microscopy based, high-content screen to evaluate 1114 FDA approved drugs for the potential to increase expression of the solid tumor antigen B7-H3 on the surface of osteosarcoma cells. Western blot, RT-qPCR, siRNA knockdown and flow cytometry assays were used to validate screening results and identify mechanisms of drug-induced B7-H3 upregulation. Cytokine and cytotoxicity assays were used to determine if drug pre-treatment enhanced B7-H3-CAR T cell effector function. Results: Fifty-five drugs were identified to increase B7-H3 expression on the surface of LM7 osteosarcoma cells using a novel high-content, high-throughput screen. One drug, ingenol-3-angelate (I3A), increased B7-H3 expression by up to 100%, and was evaluated in downstream experiments. Validation assays confirmed I3A increased B7-H3 expression in a biphasic dose response and cell dependent fashion. Mechanistic studies demonstrated that I3A increased B7-H3 (CD276) mRNA, total protein, and cell surface expression via protein kinase C alpha activation. Functionally, I3A induced B7-H3 expression enhanced B7-H3-CAR T cell function in cytokine production and cytotoxicity assays. Conclusions: This study demonstrates a novel high-content and high-throughput screen can identify drugs to enhance CAR T cell activity. This and other high-content technologies will pave the way to develop clinical trials implementing rational drug plus CAR T cell combinatorial therapies. Importantly, the technique could also be repurposed for an array of basic and translational research applications where drugs are needed to modulate cell surface protein expression.
MeSH term(s)	Humans ; Protein Kinase C-alpha/metabolism ; B7 Antigens/genetics ; B7 Antigens/metabolism ; Osteosarcoma/metabolism ; Bone Neoplasms/pathology ; T-Lymphocytes ; Cytokines/metabolism ; Cell Line, Tumor ; Diterpenes
Chemical Substances	ingenol (IC77UZI9G8) ; Protein Kinase C-alpha (EC 2.7.11.13) ; B7 Antigens ; Cytokines ; CD276 protein, human ; Diterpenes
Language	English
Publishing date	2024-04-01
Publishing country	England
Document type	Journal Article
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/s13046-024-03022-x
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Article ; Online: Development of BODIPY FL VH032 as a High-Affinity and Selective von Hippel-Lindau E3 Ligase Fluorescent Probe and Its Application in a Time-Resolved Fluorescence Resonance Energy-Transfer Assay.

Lin, Wenwei / Li, Yongtao / Yang, Lei / Chen, Taosheng

ACS omega

2020 Volume 6, Issue 1, Page(s) 680–695

Abstract: The von Hippel-Lindau (VHL) tumor suppressor associates with transcription factors elongin-C and elongin-B to form the VHL-elongin-C-elongin-B protein complex and carry out its functions, such as degradation of hypoxia-inducible factors. VHL ligands are ... ...

Abstract	The von Hippel-Lindau (VHL) tumor suppressor associates with transcription factors elongin-C and elongin-B to form the VHL-elongin-C-elongin-B protein complex and carry out its functions, such as degradation of hypoxia-inducible factors. VHL ligands are used not only to modulate hypoxia-signaling pathways and potentially treat chronic anemia or ischemia but also to form bivalent ligands as proteolysis-targeting chimeras to degrade proteins for potential therapeutic applications. Sensitive and selective VHL-based binding assays are critical for identifying and characterizing VHL ligands with high-throughput screening approaches. VHL ligand-binding assays, such as isothermal titration calorimetry, surface plasmon resonance, and fluorescence polarization assays, are reported but with limitations. Isothermal titration calorimetry requires higher protein concentrations with a lower throughput than fluorescence-based assays do. Surface plasmon resonance requires protein immobilization, which introduces variation and is not suitable for testing a large number of ligands. Fluorescence polarization can be sensitive with high-throughput capability but is susceptible to assay interference, and small-molecule-based fluorescent probes are not available. We developed the first small-molecule-based high-affinity VHL fluorescent probe BODIPY FL VH032 (
Language	English
Publishing date	2020-12-29
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.0c05221
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Article ; Online: Design and Optimization of 1

Li, Yongtao / Lin, Wenwei / Chai, Sergio C / Wu, Jing / Annu, Kavya / Chen, Taosheng

Journal of medicinal chemistry

2022 Volume 65, Issue 24, Page(s) 16829–16859

Abstract: The pregnane X receptor (PXR) is a key regulator of drug metabolism. Many drugs bind to and activate PXR, causing adverse drug responses. This suggests that PXR inhibitors have therapeutic value, but potent PXR inhibitors have so far been lacking. Herein, ...

Abstract	The pregnane X receptor (PXR) is a key regulator of drug metabolism. Many drugs bind to and activate PXR, causing adverse drug responses. This suggests that PXR inhibitors have therapeutic value, but potent PXR inhibitors have so far been lacking. Herein, we report the structural optimization of a series of 1
MeSH term(s)	Pregnane X Receptor ; Receptors, Steroid/metabolism ; Drug Inverse Agonism ; Triazoles/pharmacology
Chemical Substances	Pregnane X Receptor ; Receptors, Steroid ; Triazoles
Language	English
Publishing date	2022-12-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c01640
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Article ; Online: Overcoming drug resistance by regulating nuclear receptors.

Chen, Taosheng

Advanced drug delivery reviews

2010 Volume 62, Issue 13, Page(s) 1257–1264

Abstract: Drug resistance involves multiple mechanisms. Multidrug resistance (MDR) is the leading cause of treatment failure in cancer therapy. Elevated levels of MDR proteins [members of the ATP-binding cassette (ABC) transporter family] increase cellular efflux ... ...

Abstract	Drug resistance involves multiple mechanisms. Multidrug resistance (MDR) is the leading cause of treatment failure in cancer therapy. Elevated levels of MDR proteins [members of the ATP-binding cassette (ABC) transporter family] increase cellular efflux and decrease the effectiveness of chemotherapeutic agents. As a salvage approach to overcome drug resistance, inhibitors of MDR proteins have been developed, but have had limited success mainly due to undesired toxicities. Nuclear receptors (NRs), including pregnane X receptor (PXR), regulate the expression of proteins (including MDR proteins) involved in drug metabolism and drug clearance, suggesting that it is possible to overcome drug resistance by regulating NR. This review discusses the progress in the development of MDR inhibitors, with a focus on MDR1 inhibitors. Recent development of PXR antagonists to pharmacologically modulate PXR is also reviewed. The review proposes that selectively preventing the elevation of MDR levels by regulating NRs rather than non-selectively inhibiting the MDR activity by using MDR inhibitors can be a less toxic approach to overcome drug resistance during cancer therapy.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors ; ATP Binding Cassette Transporter, Subfamily B/metabolism ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/therapeutic use ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Humans ; Molecular Targeted Therapy ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Pregnane X Receptor ; Receptors, Cytoplasmic and Nuclear/metabolism ; Receptors, Steroid/antagonists & inhibitors ; Receptors, Steroid/metabolism
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B ; Antineoplastic Agents ; Pregnane X Receptor ; Receptors, Cytoplasmic and Nuclear ; Receptors, Steroid
Language	English
Publishing date	2010-08-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639113-8
ISSN	1872-8294 ; 0169-409X
ISSN (online)	1872-8294
ISSN	0169-409X
DOI	10.1016/j.addr.2010.07.008
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Article ; Online: Hepatotoxicity of Herbal Supplements Mediated by Modulation of Cytochrome P450.

Brewer, Christopher Trent / Chen, Taosheng

International journal of molecular sciences

2017 Volume 18, Issue 11

Abstract: Herbal supplements are a significant source of drug-drug interactions (DDIs), herb-drug interactions, and hepatotoxicity. Cytochrome P450 (CYP450) enzymes metabolize a large number of FDA-approved pharmaceuticals and herbal supplements. This metabolism ... ...

Abstract	Herbal supplements are a significant source of drug-drug interactions (DDIs), herb-drug interactions, and hepatotoxicity. Cytochrome P450 (CYP450) enzymes metabolize a large number of FDA-approved pharmaceuticals and herbal supplements. This metabolism of pharmaceuticals and supplements can be augmented by concomitant use of either pharmaceuticals or supplements. The xenobiotic receptors constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) can respond to xenobiotics by increasing the expression of a large number of genes that are involved in the metabolism of xenobiotics, including CYP450s. Conversely, but not exclusively, many xenobiotics can inhibit the activity of CYP450s. Induction of the expression or inhibition of the activity of CYP450s can result in DDIs and toxicity. Currently, the United States (US) Food and Drug Administration does not require the investigation of the interactions of herbal supplements and CYP450s. This review provides a summary of herbal supplements that inhibit CYP450s, induce the expression of CYP450s, and/or whose toxicity is mediated by CYP450s.
MeSH term(s)	Animals ; Chemical and Drug Induced Liver Injury/etiology ; Cytochrome P-450 Enzyme Inhibitors/pharmacology ; Cytochrome P-450 Enzyme System/metabolism ; Dietary Supplements/toxicity ; Herb-Drug Interactions ; Humans ; Liver/drug effects ; Liver/pathology ; Mice ; Rats ; Receptors, Cytoplasmic and Nuclear/metabolism ; Receptors, Steroid/metabolism ; United States ; United States Food and Drug Administration ; Xenobiotics/metabolism
Chemical Substances	Cytochrome P-450 Enzyme Inhibitors ; Receptors, Cytoplasmic and Nuclear ; Receptors, Steroid ; Xenobiotics ; constitutive androstane receptor ; pregnane X receptor ; Cytochrome P-450 Enzyme System (9035-51-2)
Language	English
Publishing date	2017-11-08
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms18112353
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