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1.
Int J Inflam ; 2022: 2337363, 2022.
Article in English | MEDLINE | ID: mdl-35265316

ABSTRACT

Toll-like receptors (TLRs) play a critical role in innate immune system responses to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). A growing body of evidence suggests that excessive TLR-mediated innate immune system activation can lead to neuronal damage and precipitate or perpetuate neurodegenerative diseases. Among TLR subtypes, both TLR2 and TLR9 have been implicated in neurodegenerative disorders with increased expression of these receptors in the central nervous system being associated with pro-inflammatory signaling and increased burdens of pathologic aggregated proteins. In the current study, we characterized the actions of a combined TLR2/TLR9 antagonist, NPT1220-312, on pro-inflammatory signaling and cytokine release in monocyte/macrophage-derived heterologous cells, human microglia, and murine and human whole blood. NPT1220-312 potently blocked TLR2- and TLR9-mediated release of inflammatory cytokines in monocyte/macrophage cells and in human microglia. NPT1220-312 also blocked TLR2-mediated activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome including IL-1ß, IL-18, and apoptosis-associated speck-like protein containing a CARD (ASC) release to the culture medium of human differentiated macrophages. The ability of NPT1220-312 to inhibit TLR2 mediated pro-inflammatory release of chemokines and cytokines in situ was demonstrated using murine and human whole blood. Together, these findings suggest that blockade of TLR2 and TLR9 may reduce inappropriate production of pro-inflammatory cytokines and chemokines from peripheral and central immune cells and thus potentially provide therapeutic benefit in neuroinflammatory/neurodegenerative disorders.

2.
Brain ; 144(12): 3692-3709, 2021 12 31.
Article in English | MEDLINE | ID: mdl-34117864

ABSTRACT

NPT520-34 is a clinical stage, small molecule being developed for the treatment of Parkinson's disease and other neurodegenerative disorders. The therapeutic potential of NPT520-34 was first suggested by findings from cell-based assays of alpha-synuclein clearance. As reported here, NPT520-34 was subsequently evaluated for therapeutically relevant actions in a transgenic animal model of Parkinson's disease that overexpresses human alpha-synuclein and in an acute lipopolysaccharide-challenge model using wild-type mice. Daily administration of NPT520-34 to mThy1-alpha-synuclein (Line 61) transgenic mice for 1 or 3 months resulted in reduced alpha-synuclein pathology, reduced expression of markers of neuroinflammation, and improvements in multiple indices of motor function. In a lipopolysaccharide-challenge model using wild-type mice, a single dose of NPT520-34 reduced lipopolysaccharide-evoked increases in the expression of several pro-inflammatory cytokines in plasma. These findings demonstrate the beneficial effects of NPT520-34 on both inflammation and protein-pathology end points, with consequent improvements in motor function in an animal model of Parkinson's disease. These findings further indicate that NPT520-34 may have two complementary actions: (i) to increase the clearance of neurotoxic protein aggregates; and (ii) to directly attenuate inflammation. NPT520-34 treatment may thereby address two of the predominate underlying pathophysiological aspects of neurodegenerative disorders such as Parkinson's disease.


Subject(s)
Brain/drug effects , Motor Activity/drug effects , Neuroprotective Agents/pharmacology , Parkinsonian Disorders/pathology , Animals , Brain/pathology , Humans , Mice , Mice, Transgenic , Synucleinopathies/pathology
3.
Bioorg Med Chem Lett ; 40: 127861, 2021 05 15.
Article in English | MEDLINE | ID: mdl-33636302

ABSTRACT

Toll-like receptors (TLRs) play key role in innate immune response to Damage Associated Molecular Patterns (DAMPs) and Pathogen Associated Molecular Patterns (PAMPs). DAMP/PAMP-mediated activation of TLRs triggers NFκB signaling resulting in pro-inflammatory cytokine release. Using TLR2-Pam2CSK4 agonist co-crystal structure information, we designed and synthesized a novel series of Toll-like Receptor 2 (TLR2) lipid antagonists and identified compounds 14, 15 and 17 with sub-micromolar potency. TLR2 antagonists that we identified are stable for > 1.0 h in both gastric juice and PBS buffer and could be used as research tools.


Subject(s)
Lipids/chemistry , Oligopeptides/chemistry , Toll-Like Receptor 2/agonists , Toll-Like Receptor 2/antagonists & inhibitors , Toll-Like Receptor 9/agonists , Crystallization , Cytokines/metabolism , Drug Discovery , Humans , NF-kappa B/metabolism , Protein Binding , Signal Transduction , Structure-Activity Relationship , Toll-Like Receptor 2/chemistry , Toll-Like Receptor 9/chemistry
4.
Bioorg Med Chem Lett ; 27(5): 1311-1315, 2017 03 01.
Article in English | MEDLINE | ID: mdl-28169164

ABSTRACT

Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.


Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Drug Design , Imidazoles/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Pteridines/chemical synthesis , Animals , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , HT29 Cells , Heterografts , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Mice , Molecular Structure , Pteridines/chemistry , Pteridines/pharmacology , Structure-Activity Relationship , Polo-Like Kinase 1
5.
Bioorg Med Chem Lett ; 26(24): 5947-5950, 2016 12 15.
Article in English | MEDLINE | ID: mdl-27839918

ABSTRACT

Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.


Subject(s)
Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrrolidinones/pharmacology , Syk Kinase/antagonists & inhibitors , Animals , Antineoplastic Agents , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Mice, Inbred C57BL , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Pyrrolidinones/administration & dosage , Pyrrolidinones/chemistry , Structure-Activity Relationship , Syk Kinase/metabolism
7.
Bioorg Med Chem ; 13(9): 3141-7, 2005 May 02.
Article in English | MEDLINE | ID: mdl-15809149

ABSTRACT

A series of novel coumarin carboxamides were synthesized, and their tumor cell cytotoxic activity was investigated. These compounds specifically inhibited the growth of cancer cells that have a high level of ErbB-2 expression. Immunoprecipitation analysis of the cell lysates prepared from carboxamide treated cancer cells showed the inhibition of ErbB-2 phosphorylation suggesting the interaction of these compounds with ErbB-2 receptor. The down regulation of the kinase activity was further confirmed by performing in vitro kinase assay with recombinant ErbB-2 incubated with carboxamides. The inhibition of ErbB-2 phosphorylation correlated with down-regulation of ERK1 MAP kinase activation that is involved in proliferative signaling pathway. Furthermore, the cell-killing activity of many of these inhibitors is restricted to tumor cells with no demonstrable cytotoxicity against normal human fibroblasts suggesting that these compounds are tumor-specific.


Subject(s)
Amides/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Coumarins/chemistry , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Receptor, ErbB-2/drug effects , Amides/chemical synthesis , Amides/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Coumarins/chemical synthesis , Female , Fibroblasts/drug effects , Humans , Mitogen-Activated Protein Kinase 3/metabolism , Molecular Structure , Receptor, ErbB-2/metabolism
8.
Bioorg Med Chem Lett ; 14(15): 4093-7, 2004 Aug 02.
Article in English | MEDLINE | ID: mdl-15225733

ABSTRACT

Synthesis of coumarin 3-(N-aryl) sulfonamides was accomplished either by Knoevenagel condensation of anilinosulfonylacetic acids with suitable salicylaldehydes or by the reaction of methyl anilinosulfonylacetates with substituted salicylaldehydes in presence of a catalytic amount of a base. All the compounds tested for antiproliferative activity in different cancer cell lines have shown GI(50) values less than 100 microM.


Subject(s)
Antineoplastic Agents/chemical synthesis , Cell Survival/drug effects , Sulfonamides/chemical synthesis , Sulfonamides/toxicity , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Cell Line, Tumor , Coumarins/chemical synthesis , Coumarins/toxicity , Humans , K562 Cells , Molecular Conformation , Molecular Structure , Sulfonamides/chemistry
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