Identification and optimisation of DVL1 inhibitors targeting the PDZ domain

Proponente Antonio Coluccia - Professore Associato
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Componente Categoria
Marianna Bufano Dottorando/Assegnista/Specializzando componente non strutturato del gruppo di ricerca
Romano Silvestri Componenti strutturati del gruppo di ricerca

Dishevelled (Dvl) proteins are intracellular scaffolds protein that act as important regulators of the Wnt signalling pathway. Dvl interac through their PDZ domains with the receptor Frizzled facilitating the dissemination of the Wnt signal. The latest effect of the Wnt activation is the rescue of ß-catenin by degradation, its movement to the nucleus and the transcription of genes associated with tumorigenesis.
The Dvl family comprises 3 isoforms (Dvl1, 2 and 3). Among them Dvl1 plays an imperative role in the Wnt transcriptional activity and its altered expression has been demonstrated in various cancer types contributing to oncogenesis in the liver, colon, cervix and other tissues.
Thus, blocking the Dvl1 PDZ Frizzled interaction represents a valuable and validated approach for cancer treatment.
The aim of this research project is to carry out a virtual screening campaign to identify new small molecule able to impar the Dvl1 Frizzled interaction by targeting the PDZ domain. The compounds selected by the virtual screening will be evaluated in-vitro to have a proof of concept that studied compounds are PDZ binders. The most promising compounds will be submitted to hit-to-lead optimization cycles which implies the design, synthesis and biological evaluation of the new compounds. The hit-to-lead process will take great advantage by the application of computer driven studies such as docking and molecular dynamics etc. Also, common descriptors of drug likeness (MW, logP and solubility) will be computed to prioritize the synthesis of compounds to have faster and hopefully more successful lead compounds identification. The designed compounds will be synthesized and evaluated in a panel of cancer cells to measure the anti-cancer activity and the selectivity index.
The goal of the present research project is the identification of one or more lead compounds with potent anti-tumor activity and improved pharmacokinetic profile to move to an in-vivo animal model evaluation.

LS7_4, LS2_13

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