Marverti G, Guaitoli G, Ligabue A, Frassineti C, Monti MG, Lombardi P, Costi
MP. Distamycin A and derivatives as synergic drugs in cisplatin-sensitive and
-resistant ovarian cancer cells. Amino Acids. 2012 Feb;42(2-3):641-53. Epub 2011
Aug 4. PubMed PMID: 21814787.
Cardinale D, Guaitoli G, Tondi D, Luciani R, Henrich S, Salo-Ahen OM, Ferrari
S, Marverti G, Guerrieri D, Ligabue A, Frassineti C, Pozzi C, Mangani S, Fessas
D, Guerrini R, Ponterini G, Wade RC, Costi MP. Protein-protein interface-binding
peptides inhibit the cancer therapy target human thymidylate synthase. Proc Natl
Acad Sci U S A. 2011 Aug 23;108(34):E542-9. Epub 2011 Jul 27. Erratum in: Proc
Natl Acad Sci U S A. 2011 Sep 20;108(38):16133. PubMed PMID: 21795601; PubMed
Central PMCID: PMC3161595.
Salo-Ahen OM, Wade RC. The active-inactive transition of human thymidylate
synthase: targeted molecular dynamics simulations. Proteins. 2011
Oct;79(10):2886-99. doi: 10.1002/prot.23123. Epub 2011 Aug 22. PubMed PMID:
Carosati E, Sforna G, Pippi M, Marverti G, Ligabue A, Guerrieri D, Piras S,
Guaitoli G, Luciani R, Costi MP, Cruciani G. Ligand-based virtual screening and
ADME-tox guided approach to identify triazolo-quinoxalines as folate cycle
inhibitors. Bioorg Med Chem. 2010 Nov 15;18(22):7773-85. Epub 2010 Oct 1. PubMed
Garg D, Henrich S, Salo-Ahen OM, Myllykallio H, Costi MP, Wade RC. Novel
approaches for targeting thymidylate synthase to overcome the resistance and
toxicity of anticancer drugs. J Med Chem. 2010 Sep 23;53(18):6539-49. Review.
PubMed PMID: 20527892.
Costi MP, Zeillinger R. Drug resistance in ovarian cancer: biomarkers and
treatments Highlights from the DROC meeting held in Modena (Italy) on the 19th
and 20th of February 2009. Scientific topics discussed at the meeting are
reported in the present issue. Gynecol Oncol. 2010 May;117(2):149-51. PubMed
Marverti G, Ligabue A, Guerrieri D, Paglietti G, Piras S, Costi MP, Farina D,
Frassineti C, Monti MG, Moruzzi MS. Spermidine/spermine N1-acetyltranferase
modulation by novel folate cycle inhibitors in cisplatin-sensitive and -resistant
human ovarian cancer cell lines. Gynecol Oncol. 2010 May;117(2):202-10. Epub 2010
Jan 19. PubMed PMID: 20031193.
Genovese F, Ferrari S, Guaitoli G, Caselli M, Costi MP, Ponterini G.
Dimer-monomer equilibrium of human thymidylate synthase monitored by fluorescence
resonance energy transfer. Protein Sci. 2010 May;19(5):1023-30. PubMed PMID:
20306493; PubMed Central PMCID: PMC2868244.
Cardinale D, Salo-Ahen OM, Guaitoli G, Ferrari S, Venturelli A, Franchini S,
Battini R, Ponterini G, Wade RC, Costi MP. Design and characterization of a
mutation outside the active site of human thymidylate synthase that affects
ligand binding. Protein Eng Des Sel. 2010 Feb;23(2):81-9. Epub 2009 Dec 2. PubMed
Henrich S, Salo-Ahen OM, Huang B, Rippmann FF, Cruciani G, Wade RC.
Computational approaches to identifying and characterizing protein binding sites
for ligand design. J Mol Recognit. 2010 Mar-Apr;23(2):209-19. PubMed PMID:
Cardinale D, Salo-Ahen OM, Ferrari S, Ponterini G, Cruciani G, Carosati E,
Tochowicz AM, Mangani S, Wade RC, Costi MP. Homodimeric enzymes as drug targets.
Curr Med Chem. 2010;17(9):826-46. Review. PubMed PMID: 20156173.
Marverti G, Ligabue A, Paglietti G, Corona P, Piras S, Vitale G, Guerrieri D,
Luciani R, Costi MP, Frassineti C, Moruzzi MS. Collateral sensitivity to novel
thymidylate synthase inhibitors correlates with folate cycle enzymes impairment
in cisplatin-resistant human ovarian cancer cells. Eur J Pharmacol. 2009 Aug
1;615(1-3):17-26. Epub 2009 May 14. PubMed PMID: 19446547.
Papers in preparation
Perturbation of the oligomeric state of the human Thymidylate Synthase obligate homodimer by mutagenesis. Outi Salo-Ahen, Daniela Cardinale, Glauco Ponterini, Stefania Ferrari, Anna Tochowicz, Cecilia Pozzi, Silvia Franchini, Yap Boum, Stefano Mangani, Robert Stroud, Hannu Myllykallio, Maria Paola Costi. Rebecca C. Wade.. In preparation.
Interactions of HOECHST 33258 with thymidylate synthase mRNA Divta Garg, Alexander Beribisky, Allessio Ligabue, Gaetano Marverti, Michael Sattler, Rebecca Wade
Comparison of electrostatic properties of thymidylate synthases. Divita Garg, Rebecca Wade. Status: in preparation
NMR study of a TS RNA complex. Divita Garg, Michael Sattler, Rebecca Wade. Status: in preparation
Fragment-based discovery of dUMP induced shift towards the dimer interface of hTS. Leone R., Calò S., Luciani R., Mangani S., Costi M.P. In preparation.
Thermodynamic studies of dimeric interface peptides inhibitors of Thymidylate synthase. G.Guaitoli, Costi MP, S.Ferrari, G.Ponterini, D.Fessas.
Inhibitor of Ovarian Cancer Cells growth by Virtual Screening: A New Thiazole Derivative Targeting Human Thymidylate Synthase. Carosati, Emanuele; Tochowicz, Anna; Marverti, Gaetano; Guaitoli, Giambattista; Benedetti, Paolo; Ferrari, Stefania; Stroud,Robert; Finer-Moore, Janet; Luciani, Rosaria; Farina, Davide; Cruciani,Gabriele; Costi, Maria Paola (Journal of Medicinal Chemistry)
The inactive form of thymidylate synthase is sterically stabilized by peptide allosteric inhibitors. Guaitoli Giambattista, Outi-Salo, Divita Garg, Dimitrios Fessas, Michael Sattler, Maria Paola Costi, Rebecca Wade, Glauco Ponterini
1. Patent number: MI2008A001493. Metodo per la funzionlizzazione sito specifica di molecole proteiche. F. Genovese, S. Ferrari, M. P. Costi, G. Ponterini. Titolare: UNIMORE.
2. Patent number: 61/043,299, WO/2009/124756. Use of Aprepitant and derivatives thereof for the treatment of cancer. M. Khun, P. Bork, P. M. Costi, R. Luciani. Titolare: EMBL (Heidelberg Germany), UNIMORE.
3. Patent number: PCT/IB2009/055439. Peptides binding to the dimer interface of thymidylate synthase for the treatment of cancer. M. P.Costi, G. Ponterini, G. Marverti, D. Cardinale, A. Venturelli, S. Ferrari. Titolare: UNIMORE, EML. The present invention relates to peptides binding to the thymidylate synthase protein, in particular to human thymidylate synthase (hTS) protein, for the treatment of cancer. The present invention relates to peptides that can bind at a binding site located at the interface of thymdylate synthase protein. These peptides range from 3 to 10, preferably 4-8 amino acids and have a sequence that binds to each subunit of the thymidylate synthase dimer at the level of dimer interface, stabilizing the dimeric inactive form of the thymdylate synthase enzyme. In addition, the present invention relates to pharmaceutical compositions comprising these compounds as active agents, and uses thereof for the treatment of cancer and to reverse or/and be active in cancer drug resistance
4. Patent number: MI2009A002117. Struttura del cristallo del complesso di Timidilato Sintetasi (TS) con un ligando. S. Mangani, C. Pozzi, S. Ferrari, M. P. Costi. Titolare: UNIMORE , Università di Siena. The inventors have discovered that some "small" peptides with a sequence consisting of 3 to 10 amino acids inhibit Thymidylate synthase protein by binding to a new site located at the interface of dimerization of the protein able to stabilize the inactive conformation of the protein. The discovery of this new binding site and of the peptide that can bind to it made it possible to verify the existence of a new mechanism of inhibition of tumor cells (particularly ovarian cancer cells) in which the catalytic function of Thymidylate synthase is inhibited (through stabilization of its inactive form) without at the same time, blocking its function of gene translation. This new mechanism allows to avoid the accumulation of high concentrations of Thymidylate synthase in cancer cells, responsible for the onset of classic drug-resistant to platinum-based drugs. Consequently, this discovery helps provide a new tool for designing new Thymidylate synthase inhibitors useful in the treatment of cancer and particularly advantageous to reverse the resistance of tumor cells to traditional anticancer agents. From the practical point of view, the patent application on peptides find use in the marketing of specific inhibitors for therapeutic indications described above.
5. Patent number: US Pat Appl US12/285,901 (PCT/EP/2009/062815) to Naxospharma srl, filed in US 16/10/2008 , “Method and intermediates for preparing 2-alkoxy and 2-aryloxy estrogen compounds” The subject of the present invention is a method for preparing 2-alkoxy and 2-aryloxyestrogen compounds, and the intermediate compounds prepared during the use of this method, which intermediate compounds have therapeutic utility and are useful intermediates in the synthesis of other physiologically active compounds. In particular, the description relates to 2-methoxyestradiol, an antitumour agent currently in advanced clinical trial for the treatment of, inter alia, ovarian cancer. The new method was devised for preparing the compound to be used as a reference in biological tests.
6. Patent number: US Pat Appl 12/458,657 to Naxospharma srl, filed in US 20/07/2009, “ Benzoquinolizinium salt derivatives as anticancer agents”. The present invention relates to benzoquinolizinium salt derivatives (berberine derivatives) and to processes for the preparation of said compounds. The invention also encompass pharmaceutical compositions containing said derivatives and the use of said compounds for the manufacture of medicaments suitable for the treatment of cancerous diseases.