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Digital archive of theses discussed at the University of Pisa


Thesis etd-05122017-111032

Thesis type
Tesi di laurea magistrale LM5
Thesis title
Design and synthesis of novel indazole-based GRK2 inhibitors
Course of study
relatore Prof.ssa Taliani, Sabrina
relatore Dott.ssa Barresi, Elisabetta
  • GPCR
  • GRK2
  • indazole
Graduation session start date
G-protein coupled receptor 2(GRK2) is a serine/threonine kinase that is ubiquitously expressed in many tissues and regulates many intracellular mechanisms.
GRK2 partecipates with arrestin in the regulation of G-protein-coupled-receptors (GPCR), a family of seven transmembranal proteins of physiological importance, by triggering receptor desensitization from G proteins and GPCR internalization upon continuos agonists stimulation. GRK2 is also responsible of phosphorylation of non-GPCR substrates that are involved in a great number of intracellular and extracellular mechanisms, that regulate signal transduction of different pathways, thus suggesting the relevant role of this kinase as an "effector" protein. In this view, GRK2 up- and down-regulation is closely related with several pathological disorders. GRK2 plays an importan role in the manteinance of heart function and structure; thus, this kinase is involved in many cardiovascular diseases.
Furthermore, this kinase is implicated in cellular growth and development, as it regulates epidermal growth factor receptors (EGFR) signaling; GRK2 is up-regulated in breast cancer cell lines in spontaneous tumors in mice, and in a proportion of invasive ductal carcinoma patients. GRK2 up-regulation can lead to changes in insulin signaling cascade, which can translate in insulin resistance. GRK2 altered levels also partecipate in degree of cognitive functions tipically observed in Alzheimer's disease. Based on the observation that GRK2 can represent a potential target for the treatment of numerous pathological diseases, in recent years, researchers have focused their attention on the development of inhibitor molecules endowed with high affinity and selectivity toward this protein. In this scenario, this thesis work aims to design and synthesize new indazole-based derivates as GRK2 inhibitors; the decoration pattern of the central scaffold was driven by molecular modelling studies in order to mimic the contact and the orientations of the key aminoacid side chains implied in the protein-protein binding.