scholarly journals Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis

2008 ◽  
Vol 58 (12) ◽  
pp. 3765-3775 ◽  
Author(s):  
John W. Rice ◽  
James M. Veal ◽  
R. Patrick Fadden ◽  
Amy F. Barabasz ◽  
Jeffrey M. Partridge ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Small Molecule ◽  
Inflammatory Disease ◽  
Small Molecule Inhibitors ◽  
Disease Pathways

scholarly journals Small Molecule Inhibitors in the Treatment of Rheumatoid Arthritis and Beyond: Latest Updates and Potential Strategy for Fighting COVID-19

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1876
Author(s):  
Magdalena Massalska ◽  
Wlodzimierz Maslinski ◽  
Marzena Ciechomska
Keyword(s):  
Rheumatoid Arthritis ◽  
Small Molecule ◽  
Viral Entry ◽  
Small Molecule Inhibitors ◽  
Large Family ◽  
Downstream Signaling ◽  
Wide Range ◽  
Synthetic Dmards ◽  
Potential Strategy ◽  
Inflammatory Molecules

The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, which are essential in downstream signaling of pro-inflammatory molecules. This review highlights current challenges associated with the treatment of RA using small molecule inhibitors targeting intracellular JAKs/MAPKs/NF-κB/SYK-BTK signaling pathways. Indeed, we have provided the latest update on development of small molecule inhibitors, their clinical efficacy and safety as a strategy for RA treatment. On the other hand, we have highlighted the risk and adverse effects of tsDMARDs administration including, among others, infections and thromboembolism. Therefore, performance of blood tests or viral infection screening should be recommended before the tsDMARDs administration. Interestingly, recent events of SARS-CoV-2 outbreak have demonstrated the potential use of small molecule inhibitors not only in RA treatment, but also in fighting COVID-19 via blocking the viral entry, preventing of hyperimmune activation and reducing cytokine storm. Thus, small molecule inhibitors, targeting wide range of pro-inflammatory singling pathways, may find wider implications not only for the management of RA but also in the controlling of COVID-19.

scholarly journals Identification of small molecule inhibitors of RANKL and TNF signalling as anti-inflammatory and antiresorptive agents in mice

2013 ◽  
Vol 74 (1) ◽  
pp. 220-226 ◽  
Author(s):  
Emmanuel Coste ◽  
Iain R Greig ◽  
Patrick Mollat ◽  
Lorraine Rose ◽  
Mohini Gray ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Loss ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Joint Destruction ◽  
Luciferase Reporter ◽  
Collagen Induced Arthritis ◽  
Arthritis Model ◽  
Anti Inflammatory ◽  
Systemic Bone Loss

IntroductionInflammatory joint diseases such as rheumatoid arthritis are associated with local bone erosions and systemic bone loss, mediated by increased osteoclastic activity. The receptor activator of nuclear factor (NF) κB ligand (RANKL) plays a key role in mediating inflammation-induced bone loss, whereas tumour necrosis factor (TNF) plays a central role in the inflammatory process. Here we tested whether a recently identified class of small molecule inhibitors of RANKL signalling (ABD compounds) also affect TNF signalling and whether these compounds inhibit inflammation in an animal model of rheumatoid arthritis.MethodsThe inhibitory effects of the ABD compounds on TNF-induced signalling were tested in mouse macrophage cultures by western blotting and in an NFκB luciferase-reporter cell line. The anti-inflammatory effects of the compounds were tested in the mouse collagen-induced arthritis model of rheumatoid arthritis.ResultsThe ABD compounds ABD328 and ABD345 both inhibited TNF-induced activation of the NFκB pathway and the extracellular signal-regulated kinase (ERK) and Jun kinase (JNK) mitogen activated protein kinases (MAPKs). When tested in the mouse collagen-induced arthritis model of rheumatoid arthritis, the compounds suppressed inflammatory arthritis, inhibited joint destruction and prevented systemic bone loss. Furthermore, one of the compounds (ABD328) showed oral activity.ConclusionsHere we describe a novel class of small molecule compounds that inhibit both RANKL- and TNF-induced NFκB and MAPK signalling in osteoclasts and macrophages, and inflammation and bone destruction in a mouse model of rheumatoid arthritis. These novel compounds therefore represent a promising new class of treatments for inflammatory diseases, such as rheumatoid arthritis.

scholarly journals SAT0016 DEVELOPMENT OF FIBROBLAST-LIKE SYNOVIOCYTE ASSAYS FOR TARGET DISCOVERY IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 938.1-938
Author(s):  
D. Ruelas ◽  
C. Chen ◽  
H. Truong ◽  
V. Lira ◽  
Y. Moazami ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Growth Factor ◽  
Synovial Fluid ◽  
Real Time ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Complete Inhibition ◽  
Cytokine Secretion ◽  
Target Discovery ◽  
Secretion Assay

Background:The rheumatoid arthritis (RA) synovium is characterized by an overabundance of fibroblast-like synoviocytes (FLS), which play a central role in the initiation and perpetuation of disease via multiple mechanisms.1FLS promote disease progression by producing high levels of proinflammatory factors, migrating to and invading cartilage and bone, and promoting self-proliferation and resistance to apoptosis. Our current understanding of the molecular mechanisms that govern FLS-mediated pathology in the synovial joint remains incomplete. Importantly, almost 30% of treatment-naïve early RA patients exhibit a strong fibroid phenotype that correlates with relatively poor response to disease-modifying anti-rheumatic drugs.2Yet, current therapies in RA are not directly aimed at FLS pathology, creating an opportunity for novel therapeutic target discovery.Objectives:Our aim is to develop a broad suite of screening-amenable assays in RA patient-derived FLS for the discovery of target pathways that control multiple pathological properties, including cytokine secretion, migration, and invasion.Methods:A sensitive high-throughput RA-FLS secretion assay was developed to examine the ability of small-molecule inhibitors to block the production of interleukin (IL)-6 and matrix metalloproteinase (MMP)-3 in response to stimuli. To create a physiologically relevant stimulus, a surrogate synovial fluid cocktail (composed of 12 factors) was defined and titrated for optimal concentration selection. Small-molecule inhibitors (N=170) of diverse biological pathways were screened using the full cocktail or individual stimulation (TNFα, IL-1α, or IL-17) to characterize assay performance. In addition, an FLS platelet-derived growth factor (PDGF)-mediated migration screening assay was developed using a live cell imaging system (IncuCyte) to quantify real-time FLS migration.Results:Due to the variability and limited volume of synovial fluid, we developed a surrogate synovial fluid cocktail to mimic the relevant stimulation of RA-FLS in the inflamed joint. The surrogate cocktail was composed of 12 factors: TNFα, IL-1α, IL-17, IFNγ, OSM, LIF, GM-CSF, IP-10, VEGF, PDGF, AREG, and FGF2. Individual titration of these factors demonstrated that only 3 stimulatory factors (TNFα, IL-1α, and IL-17) resulted in a robust increase of IL-6 production. Importantly, when all 12 factors were combined, a synergistic increase in IL-6 and MMP-3 production by FLS was observed. Screening results identified several reference compounds, including an inhibitor of transforming growth factor-b–activated kinase 1 (TAK1), that was previously reported to block cytokine secretion in FLS.3Treatment with this compound showed complete inhibition of IL-6 and MMP-3 secretion. In addition to the cytokine secretion assay, treatment of FLS with this TAK1 inhibitor resulted in almost complete inhibition of migration (Fig. 1).Conclusion:Novel FLS assays were developed to discover new targets and interrogate pathways involved in multiple disease-driving mechanisms of FLS in RA. In order to mimic the inflammatory environment present in the RA synovium, we developed a 12-factor surrogate synovial fluid cocktail. A synergistic release of both IL-6 and MMP-3 was demonstrated following cocktail stimulation compared to individual cytokines. This points to the important contribution that multiple factors play in the FLS pathogenic processes and will allow us to uncover pathway interactions that may not be captured with single stimuli. In addition, the development of a real-time, 96-well, imaging-based assay to interrogate FLS migration will allow us to identify targets that control this critical pathological function of FLS.References:[1] Bartok B, et al.J Immunol. 2014;192(5):2063-2070.[2] Humby F, et al.Ann Rheum Dis. 2019;78(6):761-772.[3] Jones DS, et al.Nat Chem Bio. 2017;13(1):38-45.Disclosure of Interests:Debbie Ruelas Employee of: Gilead, Chen Chen Employee of: Gilead, Hoa Truong Employee of: Gilead, Victor Lira Employee of: Gilead, Yasamin Moazami Employee of: Gilead, Kevin Currie Employee of: Gilead, Julie A. Di Paolo Employee of: Gilead, Helen Yu Employee of: Gilead, Gundula Min-Oo Employee of: Gilead

Discovery of a series of imidazopyrazine small molecule inhibitors of the kinase MAPKAPK5, that show activity using in vitro and in vivo models of rheumatoid arthritis

2012 ◽  
Vol 22 (6) ◽  
pp. 2266-2270 ◽  
Author(s):  
Martin J.I. Andrews ◽  
J. Andrew Clase ◽  
Gregory Bar ◽  
Giovanni Tricarico ◽  
Paul J. Edwards ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
In Vivo Models

scholarly journals New aspects of pharmacotherapy for rheumatoid arthritis: small molecule inhibitors

2012 ◽  
Vol 0 (2) ◽  
pp. 66 ◽  
Author(s):  
Evgeny Lvovich Nasonov ◽  
L N Denisov ◽  
M.L. I.G. Stanislav
Keyword(s):  
Rheumatoid Arthritis ◽  
Small Molecule ◽  
Small Molecule Inhibitors
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