Lynn Resnick
Princeton University
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Featured researches published by Lynn Resnick.
Neuropharmacology | 2010
Robert H. Ring; Lee E. Schechter; Sarah K. Leonard; Jason M. Dwyer; Brian Platt; Radka Graf; Steven M. Grauer; Claudine Pulicicchio; Lynn Resnick; Zia Rahman; Stacey J. Sukoff Rizzo; Bin Luo; Chad E. Beyer; Sheree F. Logue; Karen L. Marquis; Zoë A. Hughes; Sharon Rosenzweig-Lipson
The widely reported effects of oxytocin (OT) on CNS function has generated considerable interest in the therapeutic potential for targeting this system for a variety of human psychiatric diseases, including anxiety disorders, autism, schizophrenia, and depression. The utility of synthetic OT, as both a research tool and neurotherapeutic, is limited by the physiochemical properties inherent in most neuropeptides, notably its short half-life and poor blood brain barrier penetration. Subsequently, the discovery and development of non-peptide molecules that act as selective agonists of the oxytocin receptor (OTR) has been an important goal of the field. In this study, we report the receptor and behavioral pharmacology of WAY-267464, a first generation small-molecule OTR agonist. WAY-267464 is a high-affinity, potent, and selective (vs. V1a, V2, V1b) agonist of the OTR. In assays measuring both behavioral (four-plate test, elevated zero maze) and autonomic (stress-induced hyperthermia) parameters of the anxiety response, WAY-267464 exhibits an anxiolytic-like profile similar to OT. We have demonstrated that the anxiolytic-like profile of WAY-267464 is mediated through central sites of action. WAY-267464 also significantly reverses disruption in prepulse inhibition of the acoustic startle reflex induced by either MK-801 or amphetamine, similar to the antipsychotic-like effects previously reported for OT. Interestingly, in the mouse tail suspension test, WAY-267464 failed to produce changes in immobility that are seen with OT, raising the question of whether the antidepressant-like activity of OT may be working independently of the OTR. A selective OTR antagonist also failed to block the effects of OT on immobility in the TST. The significance of these findings for shaping the clinical development of OTR agonists is discussed.
Drug Discovery Today | 2004
Lynn Resnick; Myles Fennell
c-Jun N-terminal kinases (JNKs) have been recognized as important enzymes in cellular function. JNK3, which is predominantly found in CNS neurons, has been implicated in several neurodegenerative diseases, including Alzheimers disease, Parkinsons disease and stroke. In particular, JNK3 has been found to have an upstream role in neuronal ischemic apoptosis. JNK3 is highly expressed and activated in postmortem brains of individuals that suffered from Alzheimers disease. Furthermore, mice that are deficient in JNK3 are more resistant to 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (a neurotoxin that mimics the neuropathological characteristics of Parkinsons disease) than their wild-type littermates. Because of the involvement of JNK3 in neuronal diseases, the inhibition of this enzyme is an attractive therapeutic target.
Journal of Medicinal Chemistry | 2008
Scott Christian Mayer; Anthony F. Kreft; Boyd L. Harrison; Magid Abou-Gharbia; Madelene Antane; Suzan Aschmies; Kevin Atchison; Michael Chlenov; Derek Cecil Cole; Thomas A. Comery; George Diamantidis; John W. Ellingboe; Kristi Fan; Rocco John Galante; Cathleen Gonzales; Douglas M. Ho; Molly Hoke; Yun Hu; Donna M. Huryn; Uday Jain; Mei Jin; Kenneth Alfred Martin Kremer; Dennis M. Kubrak; Melissa Lin; Peimin Lu; Ron Magolda; Robert Martone; William M. Moore; Aram Oganesian; Menelas N. Pangalos
SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimers disease.
Neurobiology of Disease | 2010
Steven P. Braithwaite; Ralf S. Schmid; Dong Ning He; Mei-Li A. Sung; Seongeon Cho; Lynn Resnick; Michael M. Monaghan; Warren D. Hirst; Christian Essrich; Peter Reinhart; Donald C. Lo
The c-Jun N-terminal kinase (JNK) pathway potentially links together the three major pathological hallmarks of Alzheimers disease (AD): development of amyloid plaques, neurofibrillary tangles, and brain atrophy. As activation of the JNK pathway has been observed in amyloid models of AD in association with peri-plaque regions and neuritic dystrophy, as we confirm here for Tg2576/PS(M146L) transgenic mice, we directly tested whether JNK inhibition could provide neuroprotection in a novel brain slice model for amyloid precursor protein (APP)-induced neurodegeneration. We found that APP/amyloid beta (Abeta)-induced neurodegeneration is blocked by both small molecule and peptide inhibitors of JNK, and provide evidence that this neuroprotection occurs downstream of APP/Abeta production and processing. Our findings demonstrate that Abeta can induce neurodegeneration, at least in part, through the JNK pathway and suggest that inhibition of JNK may be of therapeutic utility in the treatment of AD.
Journal of Medicinal Chemistry | 2013
Donna M. Huryn; Lynn Resnick; Peter Wipf
The academic setting provides an environment that may foster success in the discovery of certain types of small molecule tools while proving less suitable in others. For example, small molecule probes for poorly understood systems, those that exploit a specific resident expertise, and those whose commercial return is not apparent are ideally suited to be pursued in a university setting. In this review, we highlight five projects that emanated from academic research groups and generated valuable tool compounds that have been used to interrogate biological phenomena: reactive oxygen species (ROS) sensors, GPR30 agonists and antagonists, selective CB2 agonists, Hsp70 modulators, and β-amyloid PET imaging agents. By taking advantage of the unique expertise resident in university settings and the ability to pursue novel projects that may have great scientific value but with limited or no immediate commercial value, probes from academic research groups continue to provide useful tools and generate a long-term resource for biomedical researchers.
Bioorganic & Medicinal Chemistry | 2009
Frank Lovering; Steve Kirincich; Weiheng Wang; Kerry Combs; Lynn Resnick; Joan Eileen Sabalski; John A. Butera; Julie Liu; Kevin D. Parris; Jean-Baptiste Telliez
A novel series of inhibitors for mitogen activated protein kinase-activated protein kinase 2 (MK-2) are reported. These squarate based inhibitors were identified via a high-throughput screen. An MK2 co-structure with the starting ligand was obtained and a structure based approach was followed to optimize potency and selectivity.
The International Journal of Neuropsychopharmacology | 2010
Jason M. Dwyer; Brian Platt; Stacey J. Sukoff Rizzo; Claudine Pulicicchio; Caitlin Wantuch; Mei-Yi Zhang; Terri Cummons; Liza Leventhal; Corey N. Bender; Jean Zhang; Dianne Kowal; Shendi Lu; S. Johannes R. Rajarao; Deborah L. Smith; Adam D. Shilling; Jianyao Wang; John A. Butera; Lynn Resnick; Sharon Rosenzweig-Lipson; Lee E. Schechter; Chad E. Beyer
Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders and some types of pain. As alpha2A-adrenoceptors regulate the release of these neurotransmitters, we examined the therapeutic potential of BRL 44408, a potent (Ki=8.5 nM) and selective (>50-fold) alpha2A-adrenoceptor antagonist (K(B)=7.9 nM). In rats, BRL 44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In a pharmacodynamic assay, pretreatment with BRL 44408 to rats responding under a fixed-ratio 30 operant response paradigm resulted in a rightward shift of the clonidine dose-response curve, an effect indicative of alpha2-adrenoceptor antagonism in vivo. Consistent with presynaptic autoreceptor antagonism and tonic regulation of neurotransmitter release, acute administration of BRL 44408 elevated extracellular concentrations of norepinephrine and dopamine, but not serotonin, in the medial prefrontal cortex. Additionally, BRL 44408, probably by inhibiting alpha2A heteroceptors, produced a significant increase in cortical levels of acetylcholine. In the forced swim test and schedule-induced polydipsia assay, BRL 44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL 44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching. Finally, BRL 44408 did not produce deficits in overall motor coordination nor alter general locomotor activity. This preclinical characterization of the neurochemical and behavioural profile of BRL 44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain.
Assay and Drug Development Technologies | 2015
Paul A. Johnston; Malabika Sen; Yun Hua; Daniel P. Camarco; Tong Ying Shun; John S. Lazo; Gabriela Mustata Wilson; Lynn Resnick; Matthew G. LaPorte; Peter Wipf; Donna M. Huryn; Jennifer R. Grandis
Signal transducer and activator of transcription factor 3 (STAT3) is hyperactivated in head and neck squamous cell carcinomas (HNSCC). Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network (MLSCN) was screened for the ability to inhibit interleukin-6 (IL-6)-induced pSTAT3 activation. For contractual reasons, the primary high-content screening (HCS) campaign was conducted over several months in 3 distinct phases; 1,068 (1.1%) primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC50 assays, and an IFNγ-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC50s against IFN-γ-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ≥70% at 20 μM; their pSTAT3 activation IC50s were ≤25 μM; they were ≥2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ≥90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC50s ≤20 μM and 13 were ≥3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC50s ≤ 20 μM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton.
Bioorganic & Medicinal Chemistry Letters | 2014
Matthew G. LaPorte; Dimas José da Paz Lima; Feng Zhang; Malabika Sen; Jennifer R. Grandis; Daniel P. Camarco; Yun Hua; Paul A. Johnston; John S. Lazo; Lynn Resnick; Peter Wipf; Donna M. Huryn
Synthesis and SAR investigation of 2-guanidinoquinazolines, initially identified in a high content screen for selective STAT3 pathway inhibitors, led to a more potent analog (11c) that demonstrated improved anti-proliferative activity against a panel of HNSCC cell lines.
Bioorganic & Medicinal Chemistry | 2009
Jun Pu; Anthony F. Kreft; Suzan Aschmies; Kevin Atchison; Joshua D Berkowitz; Thomas Joseph Caggiano; Micheal Chlenov; George Diamantidis; Boyd L. Harrison; Yun Hu; Donna M. Huryn; J. Steven Jacobsen; Mei Jin; Kerri Lipinski; Peimin Lu; Robert Martone; Koi Michele Morris; June Sonnenberg-Reines; Dave R. Riddell; Joan Eileen Sabalski; Shaiu-Ching Sun; Erik Wagner; Yiqun Wang; Zheng Xu; Hua Zhou; Lynn Resnick
gamma-Secretase inhibitors have been shown to reduce the production of beta-amyloid, a component of the plaques that are found in brains of patients with Alzheimers disease. A novel series of heterocyclic sulfonamide gamma-secretase inhibitors that reduce beta-amyloid levels in cells is reported. Several examples of compounds within this series demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative gamma-secretase substrate.