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Results: 1 to 10 of 191

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Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer.
Formisano L, Lu Y, Servetto A, Hanker AB, Jansen VM, Bauer JA, Sudhan DR, Guerrero-Zotano AL, Croessmann S, Guo Y, Ericsson PG, Lee KM, Nixon MJ, Schwarz LJ, Sanders ME, Dugger TC, Cruz MR, Behdad A, Cristofanilli M, Bardia A, O'Shaughnessy J, Nagy RJ, Lanman RB, Solovieff N, He W, Miller M, Su F, Shyr Y, Mayer IA, Balko JM, Arteaga CL
(2019) Nat Commun 10: 1373
MeSH Terms: Aminopyridines, Animals, Antineoplastic Agents, Hormonal, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Circulating Tumor DNA, Cyclin D1, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Drug Resistance, Neoplasm, Female, Fulvestrant, High-Throughput Nucleotide Sequencing, Humans, MCF-7 Cells, Mice, Mutation, Naphthalenes, Piperazines, Progression-Free Survival, Proportional Hazards Models, Protein Kinase Inhibitors, Purines, Pyrazoles, Pyridines, Quinolines, Quinoxalines, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Receptors, Estrogen, Signal Transduction, Xenograft Model Antitumor Assays
Show Abstract · Added April 2, 2019
Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.
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32 MeSH Terms
Repurposing cabozantinib to GISTs: Overcoming multiple imatinib-resistant cKIT mutations including gatekeeper and activation loop mutants in GISTs preclinical models.
Lu T, Chen C, Wang A, Jiang Z, Qi Z, Hu Z, Hu C, Liu F, Wang W, Wu H, Wang B, Wang L, Qi S, Wu J, Wang W, Tang J, Yan H, Bai M, Liu Q, Liu J
(2019) Cancer Lett 447: 105-114
MeSH Terms: Anilides, Antineoplastic Agents, Cell Line, Tumor, Drug Repositioning, Drug Resistance, Neoplasm, Gastrointestinal Stromal Tumors, Humans, Imatinib Mesylate, Mutation, Proto-Oncogene Proteins c-kit, Pyridines
Show Abstract · Added April 2, 2019
Despite of the great success of imatinib as the first-line treatment for GISTs, the majority of patients will develop drug-acquired resistance due to secondary mutations in the cKIT kinase. Sunitinib and regorafenib have been approved as the second and third line therapies to overcome some of these drug-resistance mutations; however, their limited clinical response, toxicity and resistance of the activation loop mutants still makes new therapies bearing different cKIT mutants activity spectrum profile highly demanded. Through a drug repositioning approach, we found that cabozantinib exhibited higher potency than imatinib against primary gain-of-function mutations of cKIT. Moreover, cabozantinib was able to overcome cKIT gatekeeper T670I mutation and the activation loop mutations that are resistant to imatinib or sunitinib. Cabozantinib demonstrated good efficacy in vitro and in vivo in the cKIT mutant-driven preclinical models of GISTs while displaying a long-lasting effect after treatment withdrawal. Furthermore, it also exhibited dose-dependent anti-proliferative efficacy in the GIST patient derived primary cells. Considering clinical safety and PK profile of cabozantinib, this report provides the basis for the future clinical applications of cabozantinib as an alternative anti-GISTs therapy in precision medicine.
Copyright © 2019 Elsevier B.V. All rights reserved.
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11 MeSH Terms
Discovery of Novel Central Nervous System Penetrant Metabotropic Glutamate Receptor Subtype 2 (mGlu) Negative Allosteric Modulators (NAMs) Based on Functionalized Pyrazolo[1,5- a]pyrimidine-5-carboxamide and Thieno[3,2- b]pyridine-5-carboxamide Cores.
Childress ES, Wieting JM, Felts AS, Breiner MM, Long MF, Luscombe VB, Rodriguez AL, Cho HP, Blobaum AL, Niswender CM, Emmitte KA, Conn PJ, Lindsley CW
(2019) J Med Chem 62: 378-384
MeSH Terms: Allosteric Regulation, Amides, Animals, Central Nervous System, Drug Evaluation, Preclinical, Half-Life, Humans, Inhibitory Concentration 50, Protein Isoforms, Pyrazoles, Pyridines, Pyrimidines, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
A scaffold hopping exercise from a monocyclic mGlu NAM with poor rodent PK led to two novel heterobicyclic series of mGlu NAMs based on either a functionalized pyrazolo[1,5- a]pyrimidine-5-carboxamide core or a thieno[3,2- b]pyridine-5-carboxamide core. These novel analogues possess enhanced rodent PK, while also maintaining good mGlu NAM potency, selectivity (versus mGlu and the remaining six mGlu receptors), and high CNS penetration. Interestingly, SAR was divergent between the new 5,6-heterobicyclic systems.
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Discovery of Tricyclic Triazolo- and Imidazopyridine Lactams as M Positive Allosteric Modulators.
Engers JL, Bender AM, Kalbfleisch JJ, Cho HP, Lingenfelter KS, Luscombe VB, Han C, Melancon BJ, Blobaum AL, Dickerson JW, Rook JM, Niswender CM, Emmitte KA, Conn PJ, Lindsley CW
(2019) ACS Chem Neurosci 10: 1035-1042
MeSH Terms: Allosteric Regulation, Animals, Drug Discovery, Humans, Imidazoles, Lactams, Mice, Muscarinic Agonists, Pyridines, Rats, Receptor, Muscarinic M1
Show Abstract · Added March 3, 2020
This Letter describes the chemical optimization of a new series of muscarinic acetylcholine receptor subtype 1 (M) positive allosteric modulators (PAMs) based on novel tricyclic triazolo- and imidazopyridine lactam cores, devoid of M agonism, e.g., no M ago-PAM activity, in high expressing recombinant cell lines. While all the new tricyclic congeners afforded excellent rat pharmacokinetic (PK) properties (CL < 8 mL/min/kg and t > 5 h), regioisomeric triazolopyridine analogues were uniformly not CNS penetrant ( K < 0.05), despite a lack of hydrogen bond donors. However, removal of a single nitrogen atom to afford imidazopyridine derivatives proved to retain the excellent rat PK and provide high CNS penetration ( K > 2), despite inclusion of a basic nitrogen. Moreover, 24c was devoid of M agonism in high expressing recombinant cell lines and did not induce cholinergic seizures in vivo in mice. Interestingly, all of the new M PAMs across the diverse tricyclic heterocyclic cores possessed equivalent CNS MPO scores (>4.5), highlighting the value of both "medicinal chemist's eye" and experimental data, e.g., not sole reliance (or decision bias) on in silico calculated properties, for parameters as complex as CNS penetration.
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11 MeSH Terms
Discovery and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu positive allosteric modulators that mitigate CYP1A2 induction liability.
Engers DW, Bollinger SR, Engers JL, Panarese JD, Breiner MM, Gregro A, Blobaum AL, Bronson JJ, Wu YJ, Macor JE, Rodriguez AL, Zamorano R, Conn PJ, Lindsley CW, Niswender CM, Hopkins CR
(2018) Bioorg Med Chem Lett 28: 2641-2646
MeSH Terms: Allosteric Regulation, Animals, Antiparkinson Agents, Cytochrome P-450 CYP1A2, Cytochrome P-450 CYP1A2 Inducers, Drug Discovery, Enzyme Induction, Humans, Pyrazoles, Pyridines, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson's disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu PAMs, leading to 9i (hmGlu EC = 43 nM; AhR activation = 2.3-fold).
Copyright © 2018 Elsevier Ltd. All rights reserved.
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Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors.
Bedse G, Bluett RJ, Patrick TA, Romness NK, Gaulden AD, Kingsley PJ, Plath N, Marnett LJ, Patel S
(2018) Transl Psychiatry 8: 92
MeSH Terms: Amidohydrolases, Animals, Anti-Anxiety Agents, Anxiety Disorders, Behavior, Animal, Benzodioxoles, Body Temperature, Brain, Carbamates, Endocannabinoids, Female, Locomotion, Male, Maze Learning, Mice, Inbred C57BL, Mice, Inbred ICR, Monoacylglycerol Lipases, Piperazines, Piperidines, Pyridines, Stress, Psychological
Show Abstract · Added April 12, 2019
Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light-dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light-dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG.
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Structural basis of ligand binding modes at the neuropeptide Y Y receptor.
Yang Z, Han S, Keller M, Kaiser A, Bender BJ, Bosse M, Burkert K, Kögler LM, Wifling D, Bernhardt G, Plank N, Littmann T, Schmidt P, Yi C, Li B, Ye S, Zhang R, Xu B, Larhammar D, Stevens RC, Huster D, Meiler J, Zhao Q, Beck-Sickinger AG, Buschauer A, Wu B
(2018) Nature 556: 520-524
MeSH Terms: Arginine, Binding Sites, Crystallography, X-Ray, Dihydropyridines, Diphenylacetic Acids, Humans, Inositol Phosphates, Ligands, Molecular Docking Simulation, Mutant Proteins, Mutation, Neuropeptide Y, Nuclear Magnetic Resonance, Biomolecular, Phenylurea Compounds, Protein Binding, Receptors, Neuropeptide Y, Structure-Activity Relationship, Substrate Specificity
Show Abstract · Added March 21, 2020
Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology . The NPY-Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in most mammals, namely the Y, Y, Y and Y receptors, with different affinity and selectivity . NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y receptor (YR) . A number of peptides and small-molecule compounds have been characterized as YR antagonists and have shown clinical potential in the treatment of obesity , tumour and bone loss . However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability . Here we report crystal structures of the human YR bound to the two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 Å resolution, respectively. The structures combined with mutagenesis studies reveal the binding modes of YR to several structurally diverse antagonists and the determinants of ligand selectivity. The YR structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance, photo-crosslinking and functional studies, provide insights into the binding behaviour of the agonist and for the first time, to our knowledge, determine the interaction of its N terminus with the receptor. These insights into YR can enable structure-based drug discovery that targets NPY receptors.
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mGlu and mGlu modulate distinct excitatory inputs to the nucleus accumbens shell.
Turner BD, Rook JM, Lindsley CW, Conn PJ, Grueter BA
(2018) Neuropsychopharmacology 43: 2075-2082
MeSH Terms: Animals, Cocaine, Female, Mediodorsal Thalamic Nucleus, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neuronal Plasticity, Neurons, Nucleus Accumbens, Optogenetics, Oxazoles, Prefrontal Cortex, Pyridines, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate, Synapses, Synaptic Transmission
Show Abstract · Added March 3, 2020
Glutamatergic transmission in the nucleus accumbens shell (NAcSh) is a substrate for reward learning and motivation. Metabotropic glutamate (mGlu) receptors regulate NAcSh synaptic strength by inducing long-term depression (LTD). Inputs from prefrontal cortex (PFC) and medio-dorsal thalamus (MDT) drive opposing motivated behaviors yet mGlu receptor regulation of these synapses is unexplored. We examined Group I mGlu receptor regulation of PFC and MDT glutamatergic synapses onto specific populations of NAc medium spiny neurons (MSNs) using D1tdTom BAC transgenic mice and optogenetics. Synaptically evoked long-term depression (LTD) at MDT-NAcSh synapses required mGlu but not mGlu and was specific for D1(+) MSNs, whereas PFC LTD was expressed at both D1(+) and D1(-) MSNs and required mGlu but not mGlu. Two weeks after five daily non-contingent cocaine exposures (15 mg/kg), LTD was attenuated at MDT-D1(+) synapses but was rescued by the mGlu5-positive allosteric modulator (PAM) VU0409551. These results highlight unique plasticity mechanisms regulating specific NAcSh synapses.
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Bacterial-derived Neutrophilic Inflammation Drives Lung Remodeling in a Mouse Model of Chronic Obstructive Pulmonary Disease.
Richmond BW, Du RH, Han W, Benjamin JT, van der Meer R, Gleaves L, Guo M, McKissack A, Zhang Y, Cheng DS, Polosukhin VV, Blackwell TS
(2018) Am J Respir Cell Mol Biol 58: 736-744
MeSH Terms: Airway Remodeling, Aminopyridines, Animals, Bacillus, Benzamides, Cyclopropanes, Disease Models, Animal, Mice, Inbred C57BL, Mice, Mutant Strains, Neutrophils, Pneumonia, Bacterial, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema, Receptors, Cell Surface
Show Abstract · Added March 21, 2018
Loss of secretory IgA is common in the small airways of patients with chronic obstructive pulmonary disease and may contribute to disease pathogenesis. Using mice that lack secretory IgA in the airways due to genetic deficiency of polymeric Ig receptor (pIgR mice), we investigated the role of neutrophils in driving the fibrotic small airway wall remodeling and emphysema that develops spontaneously in these mice. By flow cytometry, we found an increase in the percentage of neutrophils among CD45 cells in the lungs, as well as an increase in total neutrophils, in pIgR mice compared with wild-type controls. This increase in neutrophils in pIgR mice was associated with elastin degradation in the alveolar compartment and around small airways, along with increased collagen deposition in small airway walls. Neutrophil depletion using anti-Ly6G antibodies or treatment with broad-spectrum antibiotics inhibited development of both emphysema and small airway remodeling, suggesting that airway bacteria provide the stimulus for deleterious neutrophilic inflammation in this model. Exogenous bacterial challenge using lysates prepared from pathogenic and nonpathogenic bacteria worsened neutrophilic inflammation and lung remodeling in pIgR mice. This phenotype was abrogated by antiinflammatory therapy with roflumilast. Together, these studies support the concept that disruption of the mucosal immune barrier in small airways contributes to chronic obstructive pulmonary disease progression by allowing bacteria to stimulate chronic neutrophilic inflammation, which, in turn, drives progressive airway wall fibrosis and emphysematous changes in the lung parenchyma.
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14 MeSH Terms
Endothelial nitric oxide synthase modulates Toll-like receptor 4-mediated IL-6 production and permeability via nitric oxide-independent signaling.
Stark RJ, Koch SR, Choi H, Mace EH, Dikalov SI, Sherwood ER, Lamb FS
(2018) FASEB J 32: 945-956
MeSH Terms: Capillary Permeability, Cells, Cultured, Chronic Disease, Endothelial Cells, Gene Expression Regulation, Enzymologic, Humans, Imidazoles, Interleukin-6, Lipopolysaccharides, MAP Kinase Signaling System, Nitric Oxide, Nitric Oxide Synthase Type III, Pyridines, Toll-Like Receptor 4, Vasculitis, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added October 27, 2017
Endothelial dysfunction, characterized by changes in eNOS, is a common finding in chronic inflammatory vascular diseases. These states are associated with increased infectious complications. We hypothesized that alterations in eNOS would enhance the response to LPS-mediated TLR4 inflammation. Human microvascular endothelial cells were treated with sepiapterin or N-nitro-L-arginine methylester (L-NAME) to alter endogenous NO production, and small interfering RNA to knockdown eNOS. Alterations of endogenous NO by sepiapterin, and L-NAME provided no significant changes to LPS inflammation. In contrast, eNOS knockdown greatly enhanced endothelial IL-6 production and permeability in response to LPS. Knockdown of eNOS enhanced LPS-induced p38. Inhibition of p38 with SB203580 prevented IL-6 production, without altering permeability. Knockdown of p38 impaired NF-κB activation. Physical interaction between p38 and eNOS was demonstrated by immunoprecipitation, suggesting a novel, NO-independent mechanism for eNOS regulation of TLR4. In correlation, biopsy samples in patients with systemic lupus erythematous showed reduced eNOS expression with associated elevations in TLR4 and p38, suggesting an in vivo link. Thus, reduced expression of eNOS, as seen in chronic inflammatory disease, was associated with enhanced TLR4 signaling through p38. This may enhance the response to infection in patients with chronic inflammatory conditions.-Stark, R. J., Koch, S. R., Choi, H., Mace, E. H., Dikalov, S. I., Sherwood, E. R., Lamb, F. S. Endothelial nitric oxide synthase modulates Toll-like receptor 4-mediated IL-6 production and permeability via nitric oxide-independent signaling.
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16 MeSH Terms