Development of small molecules as potential therapeutics for Rheumatoid Arthritis

Postgraduate Thesis uoadl:2877525 89 Read counter

Κατεύθυνση Μοριακή Βιοϊατρική - Μηχανισμοί Ασθενειών, Μοριακές και Κυτταρικές θεραπείες και Βιοκαινοτομία
Library of the School of Health Sciences
Deposit date:
Nikolakis Dimitrios
Supervisors info:
Γεώργιος Κόλλιας, Καθηγητής, Ιατρική, ΕΚΠΑ
Δημήτριος Μπούμπας, Καθηγητής, Ιατρική, ΕΚΠΑ
Παναγιώτης Βεργίνης, Ερευνητής Γ', Ίδρυμα Ιατροβιολογικών Ερευνών Ακαδημίας Αθηνών
Original Title:
Development of small molecules as potential therapeutics for Rheumatoid Arthritis
Translated title:
Development of small molecules as potential therapeutics for Rheumatoid Arthritis
Chronic inflammatory diseases such as Rheumatoid Arthritis (RA), psoriasis and intestinal inflammation affect a total of 2-3% of the worldwide population. Regarding the diseases’ etiology, a variety of factors have been documented to contribute, including genetic and environmental background of the individuals. The current therapies used in clinic include the Disease-Modifying Antirheumatic Drugs (DMARDs) and the Non-Steroid Anti-Inflammatory drugs (NSAIDs). In more severe cases, and after studies that proved the pathogenic role of TNF in these diseases, anti-TNF monoclonal antibodies are prescribed. Although biological agents are very efficient in remitting the disease, they are associated with several drawbacks, including high cost, inadequate clinical response, parenteral administration, as well as increased risk of several infections, due to the progressively diminished immune response. Therefore, there is a clear need for per os administered, welltolerated, inexpensive drugs to treat RA and other diseases related to pathogenic TNF.
In this project we aim to identify new small molecules inhibitors for the treatment of chronic inflammatory diseases. To do so, we used two different approaches. The first was based on Synovial fibroblasts, a cell type that has been shown to underlie the pathogenic mechanisms of TNF dependent RA. The publicly available database L1000CDS2 was used to identify small molecules that can reverse the diseased SFs signature. L1000CDS2 proposed two kind of compounds a. an already approved antiphychotic drug and b. kinase inhibitors, targeting the kinases PLK-1 (polo-like kinase-1) and MnK-1/2. The second chemoinformatic structure based approach tried to identify small molecules that could serve as inhibitors of tpl-2 (tumor progressor locus-2) kinase as it has been shown that its activation promotes inflammatory response, in a macrophage dependent manner.
Main subject category:
Health Sciences
Rheumamtoid arthritis, TNF, Small molecules, Antipsychotic drug, PLK-1 kinase inhibitors, MnK-1/2 kinase inhibitor, Tpl-2 kinase inhibitors
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