 Professor
Federico Gago
University of Alcala,
Madrid
Department of Pharmacology,
University of Alcala, E-28871 Alcala de Henares, Madrid, Spain
Tel. +34 918 85 45
14 Fax +34 918 85 45 91
e-mail: federico.gago@uah.es
Research Interests
Programmed cell death,
or apoptosis, is a genetically regulated process aimed at eliminating
unwanted cells and maintaining immune homeostasis. Apoptosis defects may
cause many diseases, including cancer, autoimmunity and neurodegenerative
disorders. [1,2] Fas (APO-1/CD95), a membrane protein of the tumor necrosis
factor receptor (TNFR) family, has been shown to induce one of the pathways
of apoptosis when engaged by its specific ligand (FasL) or agonistic antibodies.
Fas functions as a homotrimer and contains a C-terminal cytoplasmic portion,
known as the death domain [3], that is essential for the transduction
of the death signal. Selective activation of Fas could be considered as
an attractive antitumoral therapy but the clinical use of Fas ligands
is limited by the toxic side effects derived from the widespread distribution
in normal tissues of Fas and TNFR.
In this context,
the ether lipid edelfosine (ET-18-OCH3, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine)
appears as an interesting lead compound for a novel class of highly
selective anticancer agents. Edelfosine has been shown to be selectively
taken up by tumor cells and to induce cancer cell death through Fas trimerization
and activation in the absence of FasL. Since normal cells are not able
to reach effective intracellular concentrations of the drug, the side
effects are insignificant.[4,5]
 The
molecular mechanism of Fas activation by edelfosine remains unknown. Our
research encompasses both 3D quantitative structure-activity relationship
(3D-QSAR) studies for a series of 21 analogues and homology modelling
of Fas. The 3D-QSAR study, which consists of a Comparative Molecular Field
Analysis (CoMFA) based on the powerful GRID/GOLPE methodology [6], is
well underway. The preliminary results are encouraging (Figure 1) and
we expect to validate the model with an external set of 6 new compounds
soon.
Our 3D molecular
model of human Fas is based on the known structures of the extracelullar
domain of TNFR, the intracellular domain of Fas, and the TRAF domain of
human TNFR-associated Factor (TRAF). Monomer association is being studied
with the FTDock program.[7] Both the monomers and the trimer will be scanned
in search of sites suitable for edelfosine binding, and we hope to derive
a detailed molecular model of the interaction.
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S. W. Science 1997, 275, 983-6.
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C., Macho, A., Muñoz, E., Modolell, M., Mollinedo, F. Br. J.
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Watson, K.A. J. Med. Chem., 1994, 37, 2589-2601.
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