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Novel Targets and Drugs for anticancer treatment

 

We have focused our attention to the identification of promising targets and to the development of novel drugs to be used as antiproliferative agents in the treatment of cancer.

Currently, we are studying as targets DNA polymerases, Terminal transferase (TdT) and non-receptiorial tyrosine kinases of the Src family (SFKs).

 

DNA polymerases and TdT

We have recently characterised different classes of non-nucleoside inhibitors of mammalian DNA polymerases α, β and λ, and of Terminal transferase (TDT):

 

Reseveratrol Derivatives (in collaboration with Prof. Lucia Anna Stivala, University of Pavia):





 

Non-nucleoside triphosphates (in collaboration with Prof. Marina Kukhanova, University of Moscow):





 

Diketo Hexenoic Acids (in collaboration with Prof. Roberto di Santo, University of Rome, La Sapienza):





 

Interestingly, the Diketo acids proved to be selective inhibitors of leukemic cells proliferation (MOLT-4).

We have also contributed to the characterization of potent inhibitors of SFKs, including dual Src/Abl inhibitors

 

 

 




Molecular model of dual Src/Abl inhibitors in the Src active site.


 

Several of these compounds proved to be very active against the Abl mutant T315I and against different tumors, also in Xenograft models in nude mice.

 

 

Selected References

 

Radi M, Brullo C, Crespan E, Tintori C, Musumeci F, Biava M, Schenone S, Dreassi E, Zamperini C, Maga G, Pagano D, Angelucci A, Bologna M, Botta M. Identification of potent c-Src inhibitors strongly affecting the proliferation of human neuroblastoma cells. Bioorg Med Chem Lett. 2011 Oct 1;21(19):5928-33. 

 

Kruewel T, Schenone S, Radi M, Maga G, Rohrbeck A, Botta M, Borlak J. Molecular characterization of c-Abl/c-Src kinase inhibitors targeted against murine tumour progenitor cells that express stem cell markers. PLoS One. 2010 Nov 30;5(11):e14143. 

 

Crespan E, Radi M, Zanoli S, Schenone S, Botta M, Maga G. Dual Src and Abl inhibitors target wild type Abl and the AblT315I Imatinib-resistant mutant with different mechanisms. Bioorg Med Chem. 2010 Jun 1;18(11):3999-4008. 

 

Manetti F, Santucci A, Locatelli GA, Maga G, Spreafico A, Serchi T, Orlandini  M, Bernardini G, Caradonna NP, Spallarossa A, Brullo C, Schenone S, Bruno O, Ranise A, Bondavalli F, Hoffmann O, Bologna M, Angelucci A, Botta M. Identification of a novel pyrazolo[3,4-d]pyrimidine able to inhibit cell proliferation of a human osteogenic sarcoma in vitro and in a xenograft model in  mice. J Med Chem. 2007 Nov 15;50(23):5579-88.

 

Di Santo R, Maga G. Human terminal deoxynucleotidyl transferases as novel targets for anticancer chemotherapy. Curr Med Chem. 2006;13(20):2353-68. 

 

Manetti F, Locatelli GA, Maga G, Schenone S, Modugno M, Forli S, Corelli F, Botta M. A combination of docking/dynamics simulations and pharmacophoric modeling to discover new dual c-Src/Abl kinase inhibitors. J Med Chem. 2006 Jun 1;49(11):3278-86. 

 

Carraro F, Naldini A, Pucci A, Locatelli GA, Maga G, Schenone S, Bruno O, Ranise A, Bondavalli F, Brullo C, Fossa P, Menozzi G, Mosti L, Modugno M, Tintori C, Manetti F, Botta M. Pyrazolo[3,4-d]pyrimidines as potent antiproliferative and proapoptotic agents toward A431 and 8701-BC cells in culture via inhibition of c-Src phosphorylation. J Med Chem. 2006 Mar 9;49(5):1549-61. 

 

Crespan E, Zanoli S, Khandazhinskaya A, Shevelev I, Jasko M, Alexandrova L, Kukhanova M, Blanca G, Villani G, Hubscher U, Spadari S, Maga G. Incorporation of non-nucleoside triphosphate analogues opposite to an abasic site by human DNA polymerases beta and lambda. Nucleic Acids Res. 2005 Jul 25;33(13):4117-27. 

 

Locatelli GA, Di Santo R, Crespan E, Costi R, Roux A, Hubscher U, Shevelev I, Blanca G, Villani G, Spadari S, Maga G. Diketo hexenoic acid derivatives are novel selective non-nucleoside inhibitors of mammalian terminal deoxynucleotidyl transferases, with potent cytotoxic effect against leukemic cells. Mol Pharmacol. 2005 Aug;68(2):538-50.

 

Locatelli GA, Savio M, Forti L, Shevelev I, Ramadan K, Stivala LA, Vannini V, Hubscher U, Spadari S, Maga G. Inhibition of mammalian DNA polymerases by resveratrol: mechanism and structural determinants. Biochem J. 2005 Jul 15;389(Pt 2):259-68.&nb

 


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