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1.
Pharmacol Res ; 125(Pt B): 188-200, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28860008

RESUMO

TNF receptor associated periodic syndrome (TRAPS) is an autoinflammatory disease caused by mutations in TNF Receptor 1 (TNFR1). Current therapies for TRAPS are limited and do not target the pro-inflammatory signalling pathways that are central to the disease mechanism. Our aim was to identify drugs for repurposing as anti-inflammatories based on their ability to down-regulate molecules associated with inflammatory signalling pathways that are activated in TRAPS. This was achieved using rigorously optimized, high through-put cell culture and reverse phase protein microarray systems to screen compounds for their effects on the TRAPS-associated inflammatory signalome. 1360 approved, publically available, pharmacologically active substances were investigated for their effects on 40 signalling molecules associated with pro-inflammatory signalling pathways that are constitutively upregulated in TRAPS. The drugs were screened at four 10-fold concentrations on cell lines expressing both wild-type (WT) TNFR1 and TRAPS-associated C33Y mutant TNFR1, or WT TNFR1 alone; signalling molecule levels were then determined in cell lysates by the reverse-phase protein microarray. A novel mathematical methodology was developed to rank the compounds for their ability to reduce the expression of signalling molecules in the C33Y-TNFR1 transfectants towards the level seen in the WT-TNFR1 transfectants. Seven high-ranking drugs were selected and tested by RPPA for effects on the same 40 signalling molecules in lysates of peripheral blood mononuclear cells (PBMCs) from C33Y-TRAPS patients compared to PBMCs from normal controls. The fluoroquinolone antibiotic lomefloxacin, as well as others from this class of compounds, showed the most significant effects on multiple pro-inflammatory signalling pathways that are constitutively activated in TRAPS; lomefloxacin dose-dependently significantly reduced expression of 7/40 signalling molecules across the Jak/Stat, MAPK, NF-κB and PI3K/AKT pathways. This study demonstrates the power of signalome screening for identifying candidates for drug repurposing.


Assuntos
Anti-Inflamatórios/farmacologia , Febre/imunologia , Fluoroquinolonas/farmacologia , Doenças Hereditárias Autoinflamatórias/imunologia , Transdução de Sinais/efeitos dos fármacos , Adulto , Linhagem Celular Tumoral , Reposicionamento de Medicamentos , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Receptores Tipo I de Fatores de Necrose Tumoral/genética
2.
J Med Chem ; 60(8): 3438-3450, 2017 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-28376306

RESUMO

There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.


Assuntos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Cães , Descoberta de Drogas , Humanos , Metilação , Inibidores de Proteínas Quinases/farmacocinética
3.
J Comput Aided Mol Des ; 31(3): 305-308, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27798721

RESUMO

Computer-aided drug design encompasses a wide variety of tools and techniques, and can be implemented with a range of organisational structures and focus in different organisations. Here we outline the computational chemistry skills within Sygnature Discovery, along with the software and hardware at our disposal, and briefly discuss the methods that are not employed and why. The goal of the group is to provide support for design and analysis in order to improve the quality of compounds synthesised and reduce the timelines of drug discovery projects, and we reveal how this is achieved at Sygnature. Impact on medicinal chemistry is vital to demonstrating the value of computational chemistry, and we discuss the approaches taken to influence the list of compounds for synthesis, and how we recognise success. Finally we touch on some of the areas being developed within the team in order to provide further value to the projects and clients.


Assuntos
Desenho Assistido por Computador , Descoberta de Drogas/métodos , Indústria Farmacêutica/métodos , Biologia Computacional , Desenho de Fármacos , Modelos Moleculares , Estrutura Molecular , Software , Relação Estrutura-Atividade
4.
J Med Chem ; 58(8): 3611-25, 2015 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-25849762

RESUMO

A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.


Assuntos
Desenho de Fármacos , Fosfofrutoquinase-2/antagonistas & inibidores , Fosfofrutoquinase-2/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Linhagem Celular , Humanos , Masculino , Camundongos , Modelos Moleculares , Fosfofrutoquinase-2/química , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Ratos Wistar , Relação Estrutura-Atividade
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