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Keywords | Ovarian cancer | thymidylate synthase inhibitor | small molecule inhibitor design |<br />
LIGHTS<br />
Small ligands to interfere with Thymidylate<br />
Synthase dimer formation as new tools<br />
for development of anti-cancer agents<br />
against ovarian carcinoma<br />
Summary<br />
Ovarian cancer is the fi fth most common cause of death from<br />
cancer in women. The standard fi rst-line treatment is a combination<br />
of paclitaxel and carboplatin or carboplatin alone.<br />
In the case of progressive disease or drug resistance treatment<br />
with platinum, either alone or in combination, especially<br />
investigational compounds should be used. The mechanisms<br />
behind acquired resistance to cisplatin (cDDP) and its derivatives<br />
are not clear yet, although it is evident that the process<br />
is multifactorial, including enhanced DNA repair. In the human<br />
ovarian carcinoma cell line A2780, a three-fold-cDDP- resistance<br />
was associated with cross-resistance to the thymidylate<br />
synthase (TS) inhibitor 5-fl uorouracil and to methotrexate,<br />
a 2.5-fold increase in TS, and an increase in the intracellular<br />
pools of the TS cofactor 5, 10-methylentetrahydrofolate and<br />
of tetrahydrofolate.<br />
The ultimate goal of LIGHTS is to directly halt tumour progression<br />
and the development of drug resistance upon<br />
treatment with platinum-derived drugs, by inhibiting the<br />
protein regulatory function of monomeric TS through small<br />
molecule cellular perturbation. The scientifi c and technological<br />
objectives will be to design small-ligand libraries to bind<br />
to the TS monomer (dimer interface) and thereby disrupt TS.<br />
The strategy will include, systems pathway analysis, protein<br />
SH-labelling to identify low-affi nity ligands, peptide mimic<br />
design and synthesis, and fi ltering for ADME properties.<br />
The multidisciplinary approach will be carried out by<br />
a Consortium integrating molecular modelling, chemistry,<br />
chemoinformatics, structural biology and pharmacology,<br />
and will apply the knowledge being created by genomics<br />
and other fi elds of basic research to the problem of discovery<br />
of anti-cancer agents. The Consortium consists of six<br />
groups from fi ve diff erent countries, including three SMEs.<br />
Problem<br />
Ovarian cancer is the fi fth most common cause of death from<br />
cancer and the most common cause of death from gynecologic<br />
cancer in women of all ages in the Western world.<br />
Single-agent carboplatin (cDDP) has been considered a reasonable<br />
option for fi rst-line chemotherapy for ovarian cancer.<br />
TREATMENT<br />
However the occurrence of resistant cell populations in the<br />
tumour, limiting the usefulness of the platinum drug, represents<br />
a growing problem. Resistant cells often become refractory to<br />
the initially used drugs and are extremely diffi cult to eradicate,<br />
therefore the use of drug combinations is necessary.<br />
The combination of cDDP and antifolates such as azidothymidine<br />
(AZT), a deoxythymidine analogue or, more recently,<br />
pemetrexed (Alimta) that inhibits three enzymes in the de novo<br />
purine and pyrimidine pathways, has been shown to synergistically<br />
aff ect the growth of human ovarian carcinoma cells<br />
resistant to cDDP. Due to the role played by the enzymes of<br />
DNA synthesis and repair in the occurrence of cDDP-resistance,<br />
it seems of great priority to develop clinical reagents<br />
designed to limit the intracellular level of TS protein which is<br />
associated with clinical resistance, thus sensitising even resistant<br />
cells to the eff ects of anti-cancer drugs. The ultimate aim<br />
of LIGHTS is to directly halt tumour progression and interfere<br />
with the development of drug resistance upon treatment with<br />
platinum-derived drugs by inhibiting the protein regulatory<br />
function of TS through small molecule cellular perturbation.<br />
Aim<br />
The project is clearly oriented to directly halt the progression<br />
of ovarian cancer and to interfere with the development<br />
of drug resistance, upon treatment with platinum-derived<br />
drugs, by inhibiting the protein regulatory function of monomeric<br />
TS. The intermediate objectives are based on employing<br />
novel medicinal chemistry strategies to identify potential<br />
drug candidates with new mechanisms of action. LIGHTS<br />
specifi cally addresses early-phase medicinal chemistry<br />
issues that can critically infl uence the time schedule for<br />
obtaining an investigational drug candidate. Nevertheless it<br />
is also expected as products of our project that potential<br />
drug candidate(s) with a high-quality in vitro activity profi le<br />
can be obtained ready for in vivo pharmacology profi ling.<br />
In particular, LIGHTS objectives are:<br />
• derivation of small-ligand libraries with ligands designed<br />
to bind to the thymidylate synthase monomer/monomer<br />
interface aff ecting dimer formation and TS- mRNA inter -<br />
actions;<br />
• validation of the integrated, multidisciplinary drug design<br />
strategy necessary to achieve previous objective, which<br />
poses a highly challenging design problem. The strategy<br />
includes protein cysteine SH-labelling to identify lowaffi<br />
nity ligands, peptide mimetic design, and fi ltering for<br />
ADME properties;<br />
• identifi cation of small-ligands through in a chemicalbiology<br />
approach as eff ective perturbing agents to<br />
investigate the mechanism of resistance against a panel<br />
of cis-platinum-resistant ovarian carcinoma cell-lines;<br />
• development of potential drug candidate(s) with new<br />
mechanisms of action for further development as safer<br />
therapeutic agent(s) for the treatment of ovarian carcinoma.<br />
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