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Tesi etd-03172014-205415


Thesis type
Tesi di laurea specialistica LC5
Author
PATRIARCHI, MANUEL
email address
patriarchi84@yahoo.it
URN
etd-03172014-205415
Title
Emerging anticancer targets for the design and synthesis of small molecule inhibitors: ADAM 10 and MDM2.
Struttura
FARMACIA
Corso di studi
CHIMICA E TECNOLOGIA FARMACEUTICHE
Commissione
relatore Prof. Rossello, Armando
relatore Dott.ssa Nuti, Elisa
Parole chiave
  • ligands
  • inhibitor
  • mdm2
  • p53
  • adam 10
  • adams
Data inizio appello
09/04/2014;
Consultabilità
completa
Riassunto analitico
ADAMs (a disintegrin and metalloproteinase) are a family of type I transmembrane glycoproteins emerging as the major proteinase family that mediates ectodomain shedding of various cell surface proteins such as growth factors, receptors and their ligands, cytokines, and cell adhesion molecules. Recently, specific ADAMs were implicated in a number of diseases and in particular ADAM-10 overexpression was found to be involved in cancer. The pharmaceutical research has dedicated many efforts to the discovery of potent and selective inhibitors of this enzyme. Incyte Corporation in 2008 disclosed INCB 3619, a potent, selective and orally bioavailable ADAM-10 small molecule inhibitor able to block the shedding of HER ligands. In the first part of my thesis project I have synthesized new sulfonamide hydroxamate compounds, analogues of INCB3619 to be studied for their inhibitory properties (selectivity profile and potency of action) on Metzincin family (MMPs and ADAMs). In the second part of my thesis, I have developed a study on ligands active as inhibitors on MDM2-p53 interaction. P53 plays a protective roles in normal somatic tissues, constantly monitors cell integrity and homeostasis. MDM2 (murine double minute 2) regulates p53 through an autoregulatory feedback loop in which both proteins control mutually their cellular level. Low molecolar weight compounds which interacts with the deep cavity on the surface of the MDM2 molecule were designed.
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