The 67 kDa laminin receptor (67LR) is a non-integrin
receptor for laminin (LM), the major component of basement membranes.
67LR derives from homo- or hetero-dimerization of a 37 kDa cytosolic
precursor (37LRP). 67LR expression is increased in neoplastic cells
and correlates with an enhanced invasive and metastatic potential.
The correlation between 37LRP/67LR levels and tumor aggressiveness
recommends the receptor as a new promising target for cancer treatment.
We use structure-based virtual screening (SB-VS) to search for 67LR
inhibitory small molecules, by focusing on a 37LRP sequence able to
specifically bind LM.
The cell division cycle 25 (CDC25) phosphatases include CDC25A, CDC25B and CDC25C.
These three molecules are important regulators of several steps in the cell cycle,
including the activation of various cyclin-dependent kinases (CDKs).
CDC25 phosphatases are also key components of the checkpoint pathways that become
activated in the event of DNA damage. Misregulation of CDC25 phosphatases can therefore
contribute to genomic instability. In fact CDC25 proteins are overexpressed in several
human malignances. Their key roles in cell-cycle control and their abnormal expression
in cancer cells make CDC25 phosphatases ideal targets for cancer therapy.
Our research is focused on the discovery of novel CDC25 inhibitors using both
structure-based and ligand-based virtual screening approaches.
Urokinase-type plasminogen activator receptor (uPAR) binds the protease
urokinase-type plasminogen activator (uPA; also known as urokinase); uPA cleaves
plasminogen, generating the active protease plasmin, thus triggering a cascade of
proteolytic events that leads to the active degradation of extracellular matrix
(ECM) components. uPAR overexpression functions as a biomarker for cancer progression
and metastasis in many forms of human malignancy. It has been recently proposed that
uPAR can promote metastasis not only by a uPA-dependent mechanism but also through
a direct binding to vitronectin followed by activation of a specific signal transduction.
Our strategy involves the use of structure-based virtual screening to identify new potential
small molecules capable of interfering in the vitronectin–uPAR interaction.
The proteasome is a key player in one of the most fundamental cellular processes
in eukaryotes, the ubiquitin-dependent protein degradation pathway.
Proteasome presents three different catalytic subunits which are classified on
the basis of the amino acid after which they cleave the peptide bond: β1 or post-glutamyl
peptidyl hydrolase (PGPH), or caspase-like (C-L) site, which cleaves mainly after
acidic amino acids; β2 or trypsin-like (T-L), that cleaves after basic amino acids;
β5 or chymotrypsin-like (ChT-L) that cleaves after hydrophobic residues.
Most of proteasome substrates are involved in cell cycle regulation, angiogenesis
and apoptosis, therefore defects of this system can lead to an anarchic cell proliferation.
As a consequence, proteasome inhibition has been identified as a promising strategy for anticancer therapy.
Structure-based and ligand based approaches are applied for the
identification and optimization of novel proteasome inhibitors.
DNA intercalators are small molecules that can bind between adjacent base pairs
of double-stranded DNA, affording a distorted helix and affecting the activity
of processing enzymes, thus compromising the structure and physiological functions
of the macromolecule. These agents have the potential to interfere with DNA
replication and disrupt the normal function of DNA, leading to cell death.
Among chemotherapeutic drugs, DNA-intercalating agents represent a peculiar
group with excellent antitumor activity.
We employ several computational approaches such as molecular docking and quantum
mechanical calculations to provide insights into the mechanisms of action of DNA intercalating agents.
