1,199 results match your criteria off-target receptors


The sphingosine 1-phosphate receptor 2/4 antagonist JTE-013 elicits off-target effects on sphingolipid metabolism.

Sci Rep 2022 Jan 10;12(1):454. Epub 2022 Jan 10.

Molecular Therapeutics Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.

Sphingosine 1-phosphate (S1P) is a signaling lipid that has broad roles, working either intracellularly through various protein targets, or extracellularly via a family of five G-protein coupled receptors Agents that selectively and specifically target each of the S1P receptors have been sought as both biological tools and potential therapeutics. JTE-013, a small molecule antagonist of S1P receptors 2 and 4 (S1P and S1P) has been widely used in defining the roles of these receptors in various biological processes. Indeed, our previous studies showed that JTE-013 had anti-acute myeloid leukaemia (AML) activity, supporting a role for S1P in the biology and therapeutic targeting of AML. Read More

View Article and Full-Text PDF
January 2022

The skeletal muscle relaxer cyclobenzaprine is a potent non-competitive antagonist of histamine H1 receptors.

J Pharmacol Exp Ther 2022 Jan 6. Epub 2022 Jan 6.

Pharmaceutical Sciences, Mercer Univeristy, United States

Cyclobenzaprine is a tricyclic dimethylpropanamine skeletal muscle relaxant, which is used clinically to decrease muscle spasm and hypercontractility, as well as acute musculoskeletal pain. Although the absolute mechanism of action of cyclobenzaprine remains elusive, it is known to mediate its effects centrally, via inhibition of tonic somatic motor function, likely through modulation of noradrenergic and serotonergic systems. While cyclobenzaprine is effective as a muscle relaxant, greater than 30% of patients experience drowsiness and sedative/hypnotic effects, yet, the mechanisms that cause this adverse effect is also undescribed. Read More

View Article and Full-Text PDF
January 2022

PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective.

iScience 2022 Jan 4;25(1):103571. Epub 2021 Dec 4.

School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia.

Mesothelioma is a cancer that typically originates in the pleura of the lungs. It rapidly invades the surrounding tissues, causing pain and shortness of breath. We compared cell lines injected either subcutaneously or intrapleurally and found that only the latter resulted in invasive and rapid growth. Read More

View Article and Full-Text PDF
January 2022

Off-target lipid metabolism disruption by the mouse constitutive androstane receptor ligand TCPOBOP in humanized mice.

Biochem Pharmacol 2021 Dec 28;197:114905. Epub 2021 Dec 28.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address:

The constitutive androstane receptor (CAR) controls xenobiotic clearance, regulates liver glucose, lipid metabolism, and energy homeostasis. These functions have been mainly discovered using the prototypical mouse-specific CAR ligand TCPOBOP in wild-type or CAR null mice. However, TCPOBOP is reported to result in some off-target metabolic effects in CAR null mice. Read More

View Article and Full-Text PDF
December 2021

Fcγ Receptor-Dependent Internalization and Off-Target Cytotoxicity of Antibody-Drug Conjugate Aggregates.

Pharm Res 2021 Dec 27. Epub 2021 Dec 27.

Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan.

Purpose: Antibody-drug conjugates (ADCs), which are monoclonal antibodies (mAbs) conjugated with highly toxic payloads, achieve high tumor killing efficacy due to the specific delivery of payloads in accordance with mAbs' function. On the other hand, the conjugation of payloads often increases the hydrophobicity of mAbs, resulting in reduced stability and increased aggregation. It is considered that mAb aggregates have potential risk for activating Fcγ receptors (FcγRs) on immune cells, and are internalized into cells via FcγRs. Read More

View Article and Full-Text PDF
December 2021

NK Cells Armed with Chimeric Antigen Receptors (CAR): Roadblocks to Successful Development.

Cells 2021 12 1;10(12). Epub 2021 Dec 1.

Central Institute for Translational Cancer Research Technische Universität München (TranslaTUM), Department of Radiation Oncology, Klinikum Rechts der Isar, Einstein Str. 25, 81675 Munich, Germany.

In recent years, cell-based immunotherapies have demonstrated promising results in the treatment of cancer. Chimeric antigen receptors (CARs) arm effector cells with a weapon for targeting tumor antigens, licensing engineered cells to recognize and kill cancer cells. The quality of the CAR-antigen interaction strongly depends on the selected tumor antigen and its expression density on cancer cells. Read More

View Article and Full-Text PDF
December 2021

Modulating physicochemical properties of tetrahydropyridine-2-amine BACE1 inhibitors with electron-withdrawing groups: A systematic study.

Eur J Med Chem 2022 Jan 1;228:114028. Epub 2021 Dec 1.

Janssen Research & Development, Turnhoutseweg 30, B-2340, Beerse, Belgium.

A common challenge for medicinal chemists is to reduce the pK of strongly basic groups' conjugate acids into a range that preserves the desired effects, usually potency and/or solubility, but avoids undesired effects like high volume of distribution (V), limited membrane permeation, and off-target binding to, notably, the hERG channel and monoamine receptors. We faced this challenge with a 3,4,5,6-tetrahydropyridine-2-amine scaffold harboring an amidine, a key structural component of potential inhibitors of BACE1, the rate-limiting enzyme in the production of Aβ species that make up amyloid plaques in Alzheimer's disease. In our endeavor to balance potency with desirable properties to achieve brain penetration, we introduced a diverse set of groups in beta position of the amidine that modulate logD, PSA and pK. Read More

View Article and Full-Text PDF
January 2022

The acute pressure natriuresis response is suppressed by selective ETA receptor blockade.

Clin Sci (Lond) 2021 Dec 17. Epub 2021 Dec 17.

The University of Edinburgh The Queen's Medical Research Institute, Edinburgh, United Kingdom.

Hypertension is a major risk factor for cardiovascular disease.  In a significant minority of people, it develops when salt intake is increased (salt-sensitivity).  It is not clear whether this represents impaired vascular function or disruption to the relationship between blood pressure (BP) and renal salt-handling (pressure natriuresis, PN). Read More

View Article and Full-Text PDF
December 2021

Boosting Cancer Immunotherapy Via the Convenient A2AR Inhibition Using a Tunable Nanocatalyst with light-enhanced Activity.

Adv Mater 2021 Dec 15:e2106967. Epub 2021 Dec 15.

Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P. R. China.

Blockade of A2A adenosine receptors (A2AR)-adenosinergic signaling shows high potency to mobilize antitumor immunity for its in-depth involvement in immune regulation of nearly all immune cells. Available A2AR inhibition strategies are mainly based on small molecules or proteins inhibitors, yet are limited by the non-specific operation as well as the off-target toxicity. Herein, we report on the first effort to design a convenient tumor-specific A2AR inhibition strategy to improve antitumor immune responses via the spatiotemporally controlled oxygen supply by virtue of a versatile photo-modulated nanoreactor. Read More

View Article and Full-Text PDF
December 2021

Small-molecule profiling for steroid receptor activity using a universal steroid receptor reporter assay.

J Steroid Biochem Mol Biol 2021 Dec 10;217:106043. Epub 2021 Dec 10.

Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. Electronic address:

A critical step in the development of novel drug candidates for the treatment of steroid related diseases is ensuring the absence of crosstalk with steroid receptors (SRs). Establishing this SR cross-reactivity profile requires multiple reporter assays as each SR associates with its unique enhancer region, a labor intensive and time-consuming approach. To overcome this need for multi-reporter assays, we established a steroid receptor inducible luciferase reporter assay (SRi-Luc) that allows side-by-side examination of agonistic and antagonistic properties of small-molecules on all steroid receptors. Read More

View Article and Full-Text PDF
December 2021

Design, synthesis, and evaluation of phenylpiperazine-phenylacetate derivatives as rapid recovery hypnotic agents.

Bioorg Med Chem Lett 2022 Feb 8;57:128497. Epub 2021 Dec 8.

Jiangsu Institute of Marine Resources Development, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Ocean University, Lianyungang 222005, China; Wuhan Docan Pharmaceutical Co., Ltd., Wuhan 430040, China. Electronic address:

In this paper, we designed and synthesized a series of novel phenylpiperazine-phenylacetate derivatives as rapid recovery hypnotic agents. The best compound 10 had relatively high affinity for the GABA receptor and low affinity for thirteen other off-target receptors. In three animal models (mice, rats, and rabbits), compound 10 exerted potent hypnotic effects (HD = 5. Read More

View Article and Full-Text PDF
February 2022

DR-5 and DLL-4 mAb Functionalized SLNs of Gamma-Secretase Inhibitors- An Approach for TNBC Treatment.

Adv Pharm Bull 2021 Sep 19;11(4):618-623. Epub 2020 Oct 19.

Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India.

Triple-negative breast cancer (TNBC) is the most aggressive and heterogeneous cancer subtypes. High rates of metastasis, poor prognosis, and drug resistance are the major problems associated with TNBC. The current chemotherapeutics eliminate only the bulk tumor cells (non-BCSCs) and do not affect breast cancer stem cells (BCSCs). Read More

View Article and Full-Text PDF
September 2021

Unexpected Off-Target Activities for Recombinant C5a in Human Macrophages.

J Immunol 2022 01 1;208(1):133-142. Epub 2021 Dec 1.

School of Biomedical Sciences, The University of Queensland, St. Lucia, Queensland, Australia

The anaphylatoxin C5a is core effector of complement activation. C5a exerts potent proinflammatory and immunomodulatory actions through interacting with its C5a receptors, C5aR1 and C5aR2, modulating multiple signaling and functional activities of immune cells. Native C5a contains a large -linked glycosylation site at Asn, which accounts for up to 25% of its m. Read More

View Article and Full-Text PDF
January 2022

Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells.

Pathogens 2021 Nov 20;10(11). Epub 2021 Nov 20.

Department of Geography, University of Florida College of Liberal Arts and Sciences, Gainesville, FL 32611, USA.

(1) Background: There is a strong need for prevention and treatment strategies for COVID-19 that are not impacted by SARS-CoV-2 mutations emerging in variants of concern. After virus infection, host ER resident sigma receptors form direct interactions with non-structural SARS-CoV-2 proteins present in the replication complex. (2) Methods: In this work, highly specific sigma receptor ligands were investigated for their ability to inhibit both SARS-CoV-2 genome replication and virus induced cellular toxicity. Read More

View Article and Full-Text PDF
November 2021

Expanding the repertoire of methanocarba nucleosides from purinergic signaling to diverse targets.

RSC Med Chem 2021 Nov 13;12(11):1808-1825. Epub 2021 Jul 13.

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health Bethesda MD 20892-0810 USA +301 480 8422 +301 496 9024.

Nucleoside derivatives are well represented as pharmaceuticals due to their druglike physicochemical properties, and some nucleoside drugs are designed to act on receptors. The purinergic signaling pathways for extracellular nucleosides and nucleotides, consisting of adenosine receptors, P2Y/P2X receptors for nucleotides, and enzymes such as adenosine (ribo)kinase, have been extensively studied. A general modification, a constrained, bicyclic ring system (bicyclo[3. Read More

View Article and Full-Text PDF
November 2021

Off-Target Expression of Cre-Dependent Adeno-Associated Viruses in Wild-Type C57BL/6J Mice.

eNeuro 2021 Nov-Dec;8(6). Epub 2021 Nov 24.

Department of Psychology, University of Toronto Scarborough, Toronto, Ontario M1C 1A4, Canada

Adeno-associated viruses (AAVs) are a commonly used tool in neuroscience to efficiently label, trace, and/or manipulate neuronal populations. Highly specific targeting can be achieved through recombinase-dependent AAVs in combination with transgenic rodent lines that express Cre-recombinase in specific cell types. Visualization of viral expression is typically achieved through fluorescent reporter proteins (e. Read More

View Article and Full-Text PDF
December 2021

Adding Help to an HLA-A*24:02 Tumor-Reactive γδTCR Increases Tumor Control.

Front Immunol 2021 25;12:752699. Epub 2021 Oct 25.

Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands.

γδT cell receptors (γδTCRs) recognize a broad range of malignantly transformed cells in mainly a major histocompatibility complex (MHC)-independent manner, making them valuable additions to the engineered immune effector cell therapy that currently focuses primarily on αβTCRs and chimeric antigen receptors (CARs). As an exception to the rule, we have previously identified a γδTCR, which exerts antitumor reactivity against HLA-A*24:02-expressing malignant cells, however without the need for defined HLA-restricted peptides, and without exhibiting any sign of off-target toxicity in humanized HLA-A*24:02 transgenic NSG (NSG-A24:02) mouse models. This particular tumor-HLA-A*24:02-specific Vγ5Vδ1TCR required CD8αα co-receptor for its tumor reactive capacity when introduced into αβT cells engineered to express a defined γδTCR (TEG), referred to as TEG011; thus, it was only active in CD8 TEG011. Read More

View Article and Full-Text PDF
October 2021

Advances in PPARs Molecular Dynamics and Glitazones as a Repurposing Therapeutic Strategy through Mitochondrial Redox Dynamics against Neurodegeneration.

Curr Neuropharmacol 2021 Nov 9. Epub 2021 Nov 9.

Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru 570 015. India.

Peroxisome proliferator activated receptors (PPARs) activity exhibit significant implications for the development of novel therapeutic modalities against neurodegenerative diseases. PPAR-α, PPAR-β/δ, and PPAR-γ nuclear receptors expression are significantly reported in the brain, their implications in brain physiology and other neurodegenerative diseases still require extensive studies. PPAR signaling can modulate various cell signaling mechanisms involved inside the cells contributing to on- and -off target actions selectively to promote therapeutic effects as well as the adverse effects of PPAR ligands. Read More

View Article and Full-Text PDF
November 2021

Specific Protein Antigen Delivery to Human Langerhans Cells in Intact Skin.

Front Immunol 2021 21;12:732298. Epub 2021 Oct 21.

Department of Biomolecular Systems, Max-Planck-Institute of Colloids and Interfaces, Potsdam, Germany.

Immune modulating therapies and vaccines are in high demand, not least to the recent global spread of SARS-CoV2. To achieve efficient activation of the immune system, professional antigen presenting cells have proven to be key coordinators of such responses. Especially targeted approaches, actively directing antigens to specialized dendritic cells, promise to be more effective and accompanied by reduced payload due to less off-target effects. Read More

View Article and Full-Text PDF
December 2021

A highly-specific fully-human antibody and CAR-T cells targeting CD66e/CEACAM5 are cytotoxic for CD66e-expressing cancer cells in vitro and in vivo.

Cancer Lett 2022 01 3;525:97-107. Epub 2021 Nov 3.

Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Abound Bio, Pittsburgh, PA, USA. Electronic address:

Neuro-endocrine prostate cancer (NEPC) accounts for about 20% of lethal metastatic castration-resistant prostate cancer (CRPC). NEPC has the most aggressive biologic behavior of all prostate cancers and is associated with poor patient outcome. Effective treatment for NEPC is not available because NEPC exhibit distinct cell-surface expression profiles compared to other types of prostate cancer. Read More

View Article and Full-Text PDF
January 2022

Disruption of HIV-1 co-receptors CCR5 and CXCR4 in primary human T cells and hematopoietic stem and progenitor cells using base editing.

Mol Ther 2022 Jan 2;30(1):130-144. Epub 2021 Nov 2.

Medical School, Department of Pediatrics, Division of Blood and Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address:

Disruption of CCR5 or CXCR4, the main human immunodeficiency virus type 1 (HIV-1) co-receptors, has been shown to protect primary human CD4 T cells from HIV-1 infection. Base editing can install targeted point mutations in cellular genomes, and can thus efficiently inactivate genes by introducing stop codons or eliminating start codons without double-stranded DNA break formation. Here, we applied base editors for individual and simultaneous disruption of both co-receptors in primary human CD4 T cells. Read More

View Article and Full-Text PDF
January 2022

Glial PAMPering and DAMPening of Adult Hippocampal Neurogenesis.

Brain Sci 2021 Sep 29;11(10). Epub 2021 Sep 29.

Baylor College of Medicine and Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.

Adult neurogenesis represents a mature brain's capacity to integrate newly generated neurons into functional circuits. Impairment of neurogenesis contributes to the pathophysiology of various mood and cognitive disorders such as depression and Alzheimer's Disease. The hippocampal neurogenic niche hosts neural progenitors, glia, and vasculature, which all respond to intrinsic and environmental cues, helping determine their current state and ultimate fate. Read More

View Article and Full-Text PDF
September 2021

Smart Nanogatekeepers for Tumor Theranostics.

Small 2021 11 22;17(47):e2103712. Epub 2021 Oct 22.

College of Pharmacy, Anhui University of Chinese Medicine and Anhui Academy of Chinese Medicine, Hefei, 230012, China.

Nanoparticulate drug delivery systems (nano-DDSs) are required to reliably arrive and persistently reside at the tumor site with minimal off-target side effects for clinical theranostics. However, due to the complicated environment and high interstitial pressure in tumor tissue, they can return to the bloodstream and cause secondary side effects in normal organs. Recently, a number of nanogatekeepers have been engineered via structure-transformable/stable strategies to overcome this undesirable dilemma. Read More

View Article and Full-Text PDF
November 2021

Inhibition of Arginine Methylation Impairs Platelet Function.

ACS Pharmacol Transl Sci 2021 Oct 9;4(5):1567-1577. Epub 2021 Aug 9.

Department of Biomedical Sciences, University of Hull, Hull HU6 7RX, U.K.

Protein arginine methyltransferases (PRMTs) catalyze the transfer of methyl groups to arginine residues in proteins. PRMT inhibitors are novel, promising drugs against cancer that are currently in clinical trials, which include oral administration of the drugs. However, off-target activities of systemically available PRMT inhibitors have not yet been investigated. Read More

View Article and Full-Text PDF
October 2021

Design, synthesis and biological evaluation of cinnamamide-quinazoline derivatives as potential EGFR inhibitors to reverse T790M mutation.

Bioorg Chem 2021 12 12;117:105420. Epub 2021 Oct 12.

Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China; Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address:

Gatekeeper T790M mutation in EGFR is the most common factor for acquired resistance. Acrylamide-bearing 4-anilinoquinazoline scaffold are powerful irreversible inhibitors for overcoming resistance. In this work, three series of EGFR inhibitors derived from incorporation of cinnamamide into the quinazoline scaffold were designed and synthesized to reverse resistance resulting from insurgence of T790M mutation. Read More

View Article and Full-Text PDF
December 2021

ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen.

Biomed Pharmacother 2021 Dec 12;144:112274. Epub 2021 Oct 12.

Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy. Electronic address:

Sex differences in immune-mediated diseases are linked to the activity of estrogens on innate immunity cells, including macrophages. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in estrogen receptor-alpha (ERα)-dependent breast cancers and off-target indications such as infections, although the immune activity of TAM and its active metabolite, 4-OH tamoxifen (4HT), is poorly characterized. Here, we aimed at investigating the endocrine and immune activity of these SERMs in macrophages. Read More

View Article and Full-Text PDF
December 2021

Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers.

Sci Rep 2021 10 6;11(1):19877. Epub 2021 Oct 6.

Pharmaceuticals Division, Research and Development, Preclinical Research, Therapeutic Area Endocrinology, Metabolism and Reproductive Health, Bayer AG, Müllerstr. 178, 13353, Berlin, Germany.

ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Read More

View Article and Full-Text PDF
October 2021

Targeting Leukocyte Trafficking in Inflammatory Bowel Disease.

BioDrugs 2021 Sep 6;35(5):473-503. Epub 2021 Oct 6.

Faculty of Medical Sciences, Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

In the last two decades, understanding of inflammatory bowel disease (IBD) immunopathogenesis has expanded considerably. Histopathological examination of the intestinal mucosa in IBD demonstrates the presence of a chronic inflammatory cell infiltrate. Research has focused on identifying mechanisms of immune cell trafficking to the gastrointestinal tract that may represent effective gut-selective targets for IBD therapy whilst avoiding systemic immunosuppression that may be associated with off-target adverse effects such as infection and malignancy. Read More

View Article and Full-Text PDF
September 2021

Apoptotic Effects of a Thioether Analog of Vitamin K in a Human Leukemia Cell Line.

Int J Toxicol 2021 12 6;40(6):517-529. Epub 2021 Oct 6.

Laboratory of Clinical Medicine, 12976Nihon University School of Pharmacy, Chiba, Japan.

Research suggests that thioether analogs of vitamin K (VK) can act to preserve the phosphorylation of epidermal growth factor receptors by blocking enzymes (phosphatases) responsible for their dephosphorylation. Additionally, these derivatives can induce apoptosis via mitogen-activated protein kinase and caspase-3 activation, inducing reactive oxygen species (ROS) production, and apoptosis. However, vitamin K exhibits only weak inhibition of phosphatase activity, while the ability of VK to cause oxidative DNA damage has raised concerns about carcinogenicity. Read More

View Article and Full-Text PDF
December 2021

Sexually dimorphic muscarinic acetylcholine receptor modulation of contextual fear learning in the dentate gyrus.

Neurobiol Learn Mem 2021 11 2;185:107528. Epub 2021 Oct 2.

Staglin Center for Brain and Behavioral Health, Department of Psychology, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095, United States. Electronic address:

Contextual fear conditioning, where the prevailing situational cues become associated with an aversive unconditional stimulus such as electric shock, is sexually dimorphic. Males typically show higher levels of fear than females. There are two components to contextual fear conditioning. Read More

View Article and Full-Text PDF
November 2021