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Molecular Pharmacology

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https://www.readbyqxmd.com/read/29784649/small-molecular-inhibitors-targeting-protein-sumoylation-as-novel-anticancer-compounds
#1
Yanfang Yang, Zijing Xia, Xixi Wang, Xinyu Zhao, Zenghua Sheng, Yang Ye, Gu He, Liangxue Zhou, Hongxia Zhu, Ningzhi Xu, Shufang Liang
SUMOylation, one of post-translational modifications, is covalently modified on lysine residues of a target protein through an enzymatic cascade reaction similar to protein ubiquitination. Along with identification of many SUMOylated proteins, protein SUMOylation has been proven to regulate multiple biological activities including transcription, cell cycle, DNA repair and innate immunity. The dysregulation of protein SUMOylation and deSUMOylation modification is linked with carcinogenesis and tumor progression...
May 21, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29769246/small-molecule-positive-allosteric-modulators-of-the-%C3%AE-2-adrenoceptor-isolated-from-dna-encoded-libraries
#2
Seungkirl Ahn, Biswaranjan Pani, Alem W Kahsai, Eva K Olsen, Gitte Husemoen, Mikkel Vestrgaard, Lei Jin, Shuai Zhao, Laura M Wingler, Paula K Rambarat, Rishabh K Simhal, Thomas T Xu, Lillian D Sun, Paul J Shim, Dean P Staus, Li-Yin Huang, Thomas Franch, Xin Chen, Robert J Lefkowitz
Conventional drug discovery efforts at the β2 -adrenoceptor (β2 AR) have led to the development of ligands that bind almost exclusively to the receptor's hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique allosteric sites has potential for developing more specific drugs with fewer side effects than orthosteric ligands. Using our recently developed approach for screening G protein-coupled receptors (GPCRs) with DNA-encoded small molecule libraries, we have discovered and characterized the first β2 AR small molecule positive allosteric modulators (PAMs) - compound-6 [(R)-N-(4-amino-1-(4-(tert-butyl)phenyl)-4-oxobutan-2-yl)-5-(N-isopropyl-N-methylsulfamoyl)-2-((4-methoxyphenyl) thio)benzamide] and its analogs...
May 16, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29769245/pi3k-akt-mtor-signaling-pathway-and-the-biphasic-effect-of-arsenic-in-carcinogenesis
#3
Qiao Yi Chen, Max Costa
Arsenic is a naturally occurring ubiquitous metalloid found in the Earth's crust. In its inorganic form, Arsenic is highly toxic and carcinogenic, and is widely found across the globe and through out the environment. As an International Agency for Research on Cancer (IARC) defined Class I human carcinogen, arsenic has been found to cause multiple human cancers including liver, lung, urinary bladder, skin, kidney, and prostate. Mechanisms of arsenic-induced carcinogenesis remain elusive and this review specifically focuses on the role of PI3K/AKT/mTOR pathway in promoting cancer development...
May 16, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29752288/comparison-of-hepatic-nrf2-and-ahr-binding-in-2-3-7-8-tetrachlorodibenzo-p-dioxin-tcdd-treated-mice-demonstrates-nrf2-independent-pkm2-induction
#4
Rance Nault, Claire M Doskey, Kelly A Fader, Cheryl E Rockwell, Timothy R Zacharewski
2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) induces hepatic oxidative stress following activation of the aryl hydrocarbon receptor (AhR). Our recent studies showed TCDD induced pyruvate kinase muscle isoform 2 ( Pkm2 ) as a novel antioxidant response in normal differentiated hepatocytes. To investigate cooperative regulation between nuclear factor, erythroid derived 2, like 2 ( Nrf2 ) and the AhR in the induction of Pkm2 , hepatic ChIP-seq analyses were integrated with RNA-seq time course data from mice treated with TCDD for 2 - 168h...
May 11, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29743187/the-effects-of-farnesoid-x-receptor-activation-on-arachidonic-acid-metabolism-nf-kb-signaling-and-hepatic-inflammation
#5
Zhibo Gai, Michele Visentin, Ting Gui, Lin Zhao, Wolfgang E Thasler, Stephanie Hausler, Ivan Hartling, Alessio Cremonesi, Christian Hiller, Gerd A Kullak-Ublick
Inflammation has a recognized role in non-alcoholic fatty liver disease (NAFLD) progression. The present work studied the effect of high fat diet (HFD) on arachidonic acid metabolism in the liver and investigated the role of the farnesoid X receptor (FXR, NR1H4) in eicosanoid biosynthetic pathways and NF-kB signaling, major modulators of the inflammatory cascade. Mice were fed a HFD to induce NAFLD, then, treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analysis were performed on liver tissue...
May 9, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29739819/endoxifen-4-hydroxytamoxifen-and-an-estrogenic-derivative-modulate-estrogen-receptor-complex-mediated-apoptosis-in-breast-cancer
#6
Philipp Y Maximov, Balkees Abderrahman, Sean W Fanning, Surojeet Sengupta, Ping Fan, Ramona F Curpan, Daniela Maria Quintana Rincon, Jeffery A Greenland, Shyamala S Rajan, Geoffrey L Greene, V Craig Jordan
Estrogen therapy was used to treat advanced breast cancer in postmenopausal women for decades until the introduction of tamoxifen. Resistance to long-term estrogen deprivation (LTED) with tamoxifen and aromatase inhibitors used as a treatment for breast cancer inevitably occurs, but unexpectedly low dose estrogen can cause regression of breast cancer and increase disease free survival in some patients. This therapeutic effect is attributed to estrogen-induced apoptosis in LTED breast cancer. Here we describe modulation of the estrogen receptor liganded with antiestrogens (endoxifen, 4-hydroxytamoxifen) and an estrogenic triphenylethylene (TPE) EthoxyTPE (EtOXTPE) on estrogen-induced apoptosis in LTED breast cancer cells...
May 8, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29735582/thyroid-hormones-are-transport-substrates-and-transcriptional-regulators-of-organic-anion-transporting-polypeptide-2b1
#7
Henriette E Meyer Zu Schwabedissen, Celio Ferreira, Anima M Schaefer, Mouhssin Oufir, Isabell Seibert, Matthias Hamburger, Rommel G Tirona
Levothyroxine replacement therapy forms the cornerstone of hypothyroidism management. Variability in levothyroxine oral absorption may contribute to the well-recognized large interpatient differences in required dose. Moreover, levothyroxine-drug pharmacokinetic interactions are thought to be caused by altered oral bioavailability. Interestingly, little is known regarding the mechanisms contributing to levothyroxine absorption in the gastrointestinal tract. Here, we aimed to determine whether the intestinal drug uptake transporter Organic Anion Transporting Polypeptide 2B1 (OATP2B1) may be involved in facilitating intestinal absorption of thyroid hormones...
May 7, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29728448/the-temperature-dependence-of-kinetics-associated-with-drug-block-of-herg-channels-are-compound-specific-and-an-important-factor-for-proarrhythmic-risk-prediction
#8
Monique J Windley, William Lee, Jamie I Vandenberg, Adam P Hill
Current mandated preclinical tests for drug induced proarrhythmia are very sensitive, but not sufficiently specific. This has led to concern that there is a high attrition rate of potentially safe drugs that could have been beneficial to patients. The comprehensive in vitro pro-arrhythmia (CiPA) initiative has proposed new metrics based around in silico risk predictions, which are informed, amongst other things, by measures of hERG block kinetics. However, high throughput patch-clamp systems set to collect this data largely operate at ambient temperature, while the simulations for risk prediction are carried out at physiological temperature...
May 4, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29724789/ligand-specific-signaling-profiles-and-resensitization-mechanisms-of-the-neuromedin-u2-receptor
#9
Khaled Alhosaini, Omar Bahattab, Heider Qassam, John Challiss, Gary B Willars
The structurally related, but distinct neuropeptides, neuromedin U (NmU) and neuromedin S (NmS) are ligands of two G protein-coupled NmU receptors (NMU1, NMU2). Hypothalamic NMU2 regulates feeding behavior and energy expenditure and has therapeutic potential as an anti-obesity target, making an understanding of its signaling and regulation of particular interest. NMU2 binds both NmU and NmS with high affinity, resulting in receptor-ligand co-internalization. We have investigated whether receptor trafficking events post-internalization are 'biased' by the ligand bound and can therefore influence signaling function...
May 3, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29720497/molecular-mechanisms-for-species-differences-in-organic-anion-transporter-1-oat1-implications-for-renal-drug-toxicity
#10
Ling Zou, Adrian Stecula, Anshul Gupta, Bhagwat Prasad, Huan-Chieh Chien, Sook Wah Yee, Li Wang, Jashvant D Unadkat, Simone H Stahl, Katherine S Fenner, Kathleen M Giacomini
Species differences in renal drug transporters continue to plague drug development with animal models failing to adequately predict renal drug toxicity. For example, adefovir, a renally excreted antiviral drug, failed clinical studies for HIV due to pronounced nephrontoxicity in humans. In this study, we demonstrated that there are large species differences in the kinetics of interactions of a key class of antiviral drugs, acyclic nucleoside phosphonates (ANPs), with OAT1 (SLC22A6) and identified a key amino acid residue responsible for these differences...
May 2, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29695609/bitopic-binding-mode-of-an-m1-muscarinic-acetylcholine-receptor-agonist-associated-with-adverse-clinical-trial-outcomes
#11
Sophie J Bradley, Colin Molloy, Christoffer Bundgaard, Adrian J Mogg, Karen J Thompson, Louis Dwomoh, Helen E Sanger, Michael Crabtree, Simon M Brooke, Patrick M Sexton, Christian C Felder, Arthur Christopoulos, Lisa M Broad, Andrew B Tobin, Christopher J Langmead
The realisation of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702, described previously as a potent M1 receptor allosteric agonist, which showed pro-cognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side-effects...
April 25, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29691280/a-transcriptional-regulatory-network-containing-nuclear-receptors-and-lncrnas-controls-basal-and-drug-induced-expression-of-cytochrome-p450s-in-heparg-cells
#12
Liming Chen, Yifan Bao, Stephanie C Piekos, Kexin Zhu, Lirong Zhang, Xiao-Bo Zhong
Cytochrome P450 enzymes are responsible for metabolizing drugs. Expression of P450s can directly affect drug metabolism, resulting in various outcomes in therapeutic efficacy and adverse effects. Several nuclear receptors are transcription factors that can regulate expression of P450s at both basal and drug-induced levels. Some long non-coding RNAs (lncRNAs) near a transcription factor are found to participate in the regulatory functions of the transcription factors. The aim of this study is to determine whether there is a transcriptional regulatory network containing nuclear receptors and lncRNAs controlling both basal and drug-induced expression of P450s in HepaRG cells...
April 24, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29691279/assessment-of-the-molecular-mechanisms-of-action-of-novel-4-phenylpyridine-2-one-and-6-phenylpyrimidin-4-one-allosteric-modulators-at-the-m1-muscarinic-acetylcholine-receptors
#13
Emma T van der Westhuizen, Arthur Spathis, Elham Khajehali, Maneula Jorg, Shailesh N Mistry, Ben Capuano, Andrew B Tobin, Patrick M Sexton, Peter J Scammells, Celine Valant, Arthur Christopoulos
Positive allosteric modulators (PAMs) that target the M1 muscarinic acetylcholine (ACh) receptor (M1 mAChR) are potential treatments for cognitive deficits in conditions such as Alzheimer's disease and schizophrenia. We recently reported novel 4-phenylpyridine-2-one and 6-phenylpyrimidin-4-one M1 mAChR PAMs with the potential to display different modes of positive allosteric modulation and/or agonism (Mistry et al., 2016), but their molecular mechanisms of action remain undetermined. The current study compared the pharmacology of three such novel PAMs with the prototypical first-generation PAM, BQCA, in a recombinant Chinese hamster ovary (CHO) cell line stably expressing the human M1 mAChR...
April 24, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29678909/restoration-of-physiological-expression-of-5-ht6-into-the-primary-cilia-of-null-mutant-neurons-lengthens-both-primary-cilia-and-dendrites
#14
Atom J Lesiak, Matthew Brodsky, Nathalie Cohenca, Alexandra G Croicu, John F Neumaier
5-HT6 serotonin receptors are promising targets for a variety of neuropsychiatric disorders and have been linked to several cellular signaling cascades. Endogenous 5-HT6 receptors are restricted to the primary neuronal cilium, a small sensory organelle stemming from the cell body that receives numerous extra-synaptic signals. Inhibition of 5-HT6 receptors decreases cilia length in primary neuronal cultures, but the signaling mechanisms involved are still unclear. Intense overexpression of exogenous 5-HT6 receptors increases the likelihood for receptors to localize outside of the primary cilium and have been associated with changes in cilia morphology and dendritic outgrowth...
April 20, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29674524/insulin-receptor-plasma-membrane-levels-increased-by-the-progesterone-receptor-membrane-component-1
#15
Kaia K Hampton, Hilaree Frazier, Katie Anderson, Olivier Thibault, Rolf J Craven
The Insulin Receptor (IR) is a ligand-activated receptor tyrosine kinase that has a key role in metabolism, cellular survival and proliferation. Progesterone receptor membrane component 1 (PGRMC1) promotes cellular signaling via receptor trafficking, and is essential for some elements of tumor growth and metastasis. In the present study, we demonstrate that PGRMC1 co-precipitates with IR. Furthermore, we show that PGRMC1 increases plasma membrane IR levels in multiple cell lines and decreases insulin binding at the cell surface...
April 19, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29674523/efficient-high-throughput-screening-by-er-ca-2-measurement-to-identify-inhibitors-of-ryanodine-receptor-ca2-release-channels
#16
Takashi Murayama, Nagomi Kurebayashi, Mari Ikegami-Yuasa, Shuichi Mori, Yukina Suzuki, Ryunosuke Akima, Haruo Ogawa, Junji Suzuki, Kazunori Kanemaru, Hideto Oyamada, Yuji Kiuchi, Masamitsu Iino, Hiroyuki Kagechika, Takashi Sakurai
Genetic mutations in ryanodine receptors (RyRs), Ca2+-release channels in the sarcoplasmic reticulum essential for muscle contractions, cause various skeletal muscle and cardiac diseases. Because the main underlying mechanism of the pathogenesis is overactive Ca2+ release by gain-of-function of the RyR channel, inhibition of RyRs is expected to be a promising treatment for these diseases. Here, to identify inhibitors specific to skeletal muscle type 1 RyR (RyR1), we developed a novel high-throughput screening (HTS) platform using time-lapse fluorescence measurement of Ca2+ concentrations in the endoplasmic reticulum (ER) ([Ca2+]ER)...
April 19, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29669714/cannabidiol-inhibits-endocannabinoid-signaling-in-autaptic-hippocampal-neurons
#17
Alex Straiker, Michaela Dvorakova, Anaelle Zimmowitch, Ken P Mackie
Δ9-THC and cannabidiol (CBD) are two main cannabinoid constituents of marijuana and hashish. The pharmacology of Δ9-THC has been extensively studied, while our understanding of the pharmacology of CBD has remained limited, despite excitement in CBD's potential role in treating certain pediatric epilepsies and its reputation for attenuating some Δ9-THC-induced effects. It was established early on that CBD binds poorly to the orthosteric site of CB1 or CB2 cannabinoid receptors and its actions were commonly attributed to other non-cannabinoid receptor mechanisms...
April 18, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29654220/cysteine-scanning-mutagenesis-of-tm4b-4c-loop-of-glutamate-transporter-eaat1-reveals-three-conformationally-sensitive-residues
#18
Wenlong Zhang, Xiuping Zhang, Shaogang Qu
Glutamatergic synaptic transmission is terminated by members of the excitatory amino acid transporters (EAATs) that recycle glutamate from the synaptic cleft by transporting it into neuron and glial cells. To probe the structural role of the TM4b-4c loop of EAATs in glutamate transport, each of its 57 amino acid residues were mutated to cysteine. Thirteen of the single mutants have very low transport activity. Aqueous accessibility of the introduced cysteines from the remaining mutants was then explored with membrane-permeant and membrane-impermeant sulfhydryl reagents under different conditions...
April 13, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29650538/kir-channel-blockages-by-proflavine-derivatives-via-multiple-modes-of-interaction
#19
Atsushi Inanobe, Hideaki Itamochi, Yoshihisa Kurachi
Many compounds inhibit tetrameric and pseudo-tetrameric cation channels by associating with the central cavity located in the middle of the membrane plane. They traverse the ion conduction pathway from intracellular side and access to the cavity. Previously we reported that the bacteriostatic agent, proflavine, preferentially blocked a subset of Kir channels. However, the development of the inhibition of Kir1.1 by the compound was obviously different from that operating in Kir3.2 as a pore blocker. To gain mechanistic insights into the compound-channel interaction, we analyzed its chemical specificity, subunit selectivity, and voltage dependency using 13 different combinations of Kir-channel family members and 11 proflavine derivatives...
April 12, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29636377/identification-of-global-and-ligand-specific-calcium-sensing-receptor-activation-mechanisms
#20
Andrew N Keller, Irina Kufareva, Tracy M Josephs, Jiayin Diao, Vyvyan T Mai, Arthur D Conigrave, Arthur Christopoulos, Karen J Gregory, Katie Leach
Calcium sensing receptor (CaSR) positive allosteric modulators (PAMs) are therapeutically important. However, few are approved for clinical use, in part due to complexities in assessing allostery at a receptor where the endogenous agonist (extracellular calcium, Ca2+o) is present in all biological fluids. Such complexity impedes efforts to quantify and optimize allosteric drug parameters (affinity, cooperativity, efficacy) that dictate PAM structure-activity relationships (SAR). Furthermore, an under-appreciation of the structural mechanisms underlying CaSR activation hinders predictions of how PAM SAR relates to in vitro and in vivo activity...
April 10, 2018: Molecular Pharmacology
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