Projects

The CRC-AIRC (IG16977) project.

Abstract. Thymidylate synthase (TS) plays a key role in cancer development and its inhibition is very effective in different types of cancer including NSLC (non-small cell lung cancer), colorectal cancer(CRC), mesothelioma, and as recently studied in ovarian cancer. More than 1600 clinical trials have been started over the latest 5 years (www.medtrack.com) using the following drugs: pemetrexed, raltitrexed, 5Fu, pralatrexate, and methotrexate. All the therapeutical drugs exhibit similar side effects and drug resistance development, involving in particular a number of folate related proteins, folate receptor transporters, and TS as key proteins (Taddia et al., 2015 Drugs resistance uptades). The problem posed is how to solve the drug resistance problems of such widely used drugs, and how to identify new TS targeting drugs, considering that TS-targeting is one of the widely used target-directed chemotherapeutical approaches in clinical treatment (targeted therapy). The discovery of new allosteric (non-TS active site) inhibitors would be extremely important. These novel approaches will be applied to a case of colon cancer in this study.

Publications 2015-

Borsari C, Trader DJ, Tait A, Costi MP. Designing Chimeric Molecules for Drug Discovery by Leveraging Chemical Biology. J Med Chem. 2020;63(5):1908‐1928. doi:10.1021/acs.jmedchem.9b01456

Pacifico S, Santucci M, Luciani R, Saxena P, Linciano P, Ponterini G, Lauriola A, D'Arca D, Marverti G, Guerrini R, Costi MP. Cyclic Peptides Acting as Allosteric Inhibitors of Human Thymidylate Synthase and Cancer Cell Growth. Molecules. 2019 Sep 26;24(19). pii: E3493. doi: 10.3390 molecules24193493. PubMed PMID: 31561530.

Marverti G, Gozzi G, Lauriola A, Ponterini G, Belluti S, Imbriano C, Costi MP, D'Arca D. The 1,10-Phenanthroline Ligand Enhances the Antiproliferative Activity  of DNA-Intercalating Thiourea-Pd(II) and -Pt(II) Complexes Against Cisplatin-Sensitive and -Resistant Human Ovarian Cancer Cell Lines. Int J Mol Sci. 2019. Dec 4;20(24). pii: E6122. doi: 10.3390/ijms20246122.

Pozzi C, Lopresti L, Santucci M, Costi MP, Mangani S. Evidence of Destabilization of the Human Thymidylate Synthase (hTS) Dimeric Structure Induced by the Interface Mutation Q62R. Biomolecules. 2019 Apr 3;9(4). pii: E134. doi:10.3390/biom9040134. PubMed PMID: 30987202; PubMed Central PMCID: PMC6523895.

Pozzi C, Ferrari S, Luciani R, Costi MP, Mangani S. Structural and Functional Characterization of the Human Thymidylate Synthase (hTS) Interface Variant R175C, New Perspectives for the Development of hTS Inhibitors. Molecules. 2019 Apr7;24(7). pii: E1362. doi: 10.3390/molecules24071362. PubMed PMID: 30959951;PubMed Central PMCID: PMC6479699.

Pozzi C, Ferrari S, Luciani R, Tassone G, Costi MP, Mangani S. Structural Comparison of Enterococcus faecalis and Human Thymidylate Synthase Complexes with
the Substrate dUMP and Its Analogue FdUMP Provides Hints about Enzyme Conformational Variabilities. Molecules. 2019 Mar 31;24(7). pii: E1257. doi: 10.3390/molecules24071257. PubMed PMID: 30935102; PubMed Central PMCID: PMC6479881

Conteduca V, Gurioli G, Rossi L, Scarpi E, Lolli C, Schepisi G, Farolfi A, De Lisi D, Gallà V, Burgio SL, Menna C, Amadori A, Losi L, Amadori D, Costi MP, De Giorgi U. Oxaliplatin plus leucovorin and 5-fluorouracil (FOLFOX-4) as a salvage chemotherapy in heavily-pretreated platinum-resistant ovarian cancer. BMC Cancer. 2018 Dec 19;18(1):1267. doi: 10.1186/s12885-018-5180-1. PubMed PMID: 30567527;PubMed Central PMCID: PMC6300035.

Saxena P, Severi L, Santucci M, Taddia L, Ferrari S, Luciani R, Marverti G, Marraccini C, Tondi D, Mor M, Scalvini L, Vitiello S, Losi L, Fonda S, Pacifico S, Guerrini R, D'Arca D, Ponterini G, Costi MP. Conformational Propensity and Biological Studies of Proline Mutated LR Peptides Inhibiting Human Thymidylate Synthase and Ovarian Cancer Cell Growth. J Med Chem. 2018 Aug 23;61(16):7374-7380. doi: 10.1021/acs.jmedchem.7b01699. Epub 2018 Aug 13. PubMed PMID: 30035541.

Severi L, Losi L, Fonda S, Taddia L, Gozzi G, Marverti G, Magni F, Chinello C, Stella M, Sheouli J, Braicu EI, Genovese F, Lauriola A, Marraccini C, Gualandi A, D'Arca D, Ferrari S, Costi MP. Proteomic and Bioinformatic Studies for the Characterization of Response to Pemetrexed in Platinum Drug Resistant Ovarian Cancer. Front Pharmacol. 2018 May 8;9:454. doi: 10.3389/fphar.2018.00454. eCollection 2018. PubMed PMID: 29867465; PubMed Central PMCID: PMC5952181.

Rondanin R, Lettini G, Oliva P, Baruchello R, Costantini C, Trapella C, Simoni D, Bernardi T, Sisinni L, Pietrafesa M, Ponterini G, Costi MP, Vignudelli T, Luciani R, Matassa DS, Esposito F, Landriscina M. New TRAP1 and Hsp90 chaperone inhibitors with cationic components: Preliminary studies on mitochondrial targeting. Bioorg Med Chem Lett. 2018 Jul 15;28(13):2289-2293. doi: 10.1016/j.bmcl.2018.05.031. Epub 2018 May 15. PubMed PMID: 29807796.

Ferrari S, Severi L, Pozzi C, Quotadamo A, Ponterini G, Losi L, Marverti G, Costi MP. Human Thymidylate Synthase Inhibitors Halting Ovarian Cancer Growth. Vitam Horm. 2018;107:473-513. doi: 10.1016/bs.vh.2017.12.002. Epub 2018 Feb 12. Review. PubMed PMID: 29544641.

Lettini G, Maddalena F, Sisinni L, Condelli V, Matassa DS, Costi MP, Simoni D, Esposito F, Landriscina M. TRAP1: a viable therapeutic target for future cancer treatments? Expert Opin Ther Targets. 2017 Aug;21(8):805-815. doi: 10.1080/14728222.2017.1349755. Epub 2017 Jul 18. Review. PubMed PMID: 28664757.

Sacchetti F, D'Arca D, Genovese F, Pacifico S, Maretti E, Hanuskova M, Iannuccelli V, Costi MP, Leo E. Conveying a newly designed hydrophilic anti-human thymidylate synthase peptide to cisplatin resistant cancer cells: are pH-sensitive liposomes more effective than conventional ones? Drug Dev Ind Pharm. 2017 Mar;43(3):465-473. doi: 10.1080/03639045.2016.1262870. Epub 2016 Dec 26. PubMed PMID: 27885848.

Siragusa L, Luciani R, Borsari C, Ferrari S, Costi MP, Cruciani G, Spyrakis F. Comparing Drug Images and Repurposing Drugs with BioGPS and FLAPdock: The Thymidylate Synthase Case. ChemMedChem. 2016 Aug 5;11(15):1653-66. doi: 10.1002/cmdc.201600121. Epub 2016 Jul 12. PubMed PMID: 27404817.

Ponterini G, Martello A, Pavesi G, Lauriola A, Luciani R, Santucci M, Pelà M, Gozzi G, Pacifico S, Guerrini R, Marverti G, Costi MP, D'Arca D. Intracellular quantitative detection of human thymidylate synthase engagement with an unconventional inhibitor using tetracysteine-diarsenical-probe technology. Sci Rep. 2016 Jun 2;6:27198. doi: 10.1038/srep27198. PubMed PMID: 27250901; PubMed Central PMCID: PMC4890114.

Taddia L, D'Arca D, Ferrari S, Marraccini C, Severi L, Ponterini G, Assaraf YG, Marverti G, Costi MP. Inside the biochemical pathways of thymidylate synthase perturbed by anticancer drugs: Novel strategies to overcome cancer chemoresistance. Drug Resist Updat. 2015 Nov;23:20-54. doi: 10.1016/j.drup.2015.10.003. Epub 2015 Oct 31. Review. PubMed PMID: 26690339.

Sacchetti F, Marraccini C, D'Arca D, Pelà M, Pinetti D, Maretti E, Hanuskova  M, Iannuccelli V, Costi MP, Leo E. Enhanced anti-hyperproliferative activity of human thymidylate synthase inhibitor peptide by solid lipid nanoparticle delivery. Colloids Surf B Biointerfaces. 2015 Dec 1;136:346-54. doi: 10.1016/j.colsurfb.2015.09.040. Epub 2015 Sep 25. PubMed PMID: 26433347.

Salo-Ahen OM, Tochowicz A, Pozzi C, Cardinale D, Ferrari S, Boum Y, Mangani S, Stroud RM, Saxena P, Myllykallio H, Costi MP, Ponterini G, Wade RC. Hotspots in an obligate homodimeric anticancer target. Structural and functional effects of interfacial mutations in human thymidylate synthase. J Med Chem. 2015 Apr 23;58(8):3572-81. doi: 10.1021/acs.jmedchem.5b00137. Epub 2015 Apr 1. PubMed PMID: 25798950; PubMed Central PMCID: PMC4634673.

Santucci M, Vignudelli T, Ferrari S, Mor M, Scalvini L, Bolognesi ML, Uliassi E, Costi MP. The Hippo Pathway and YAP/TAZ-TEAD Protein-Protein Interaction as Targets for Regenerative Medicine and Cancer Treatment. J Med Chem. 2015 Jun 25;58(12):4857-73. doi: 10.1021/jm501615v. Epub 2015 Mar 11. Review. PubMed PMID:25719868.

Tochowicz A, Santucci M, Saxena P, Guaitoli G, Trande M, Finer-Moore J, Stroud RM, Costi MP. Alanine mutants of the interface residues of human thymidylate synthase decode key features of the binding mode of allosteric anticancer peptides. J Med Chem. 2015 Jan 22;58(2):1012-8. doi: 10.1021/jm5011176. Epub 2014 Dec 29. PubMed PMID: 25427005.