KDM5 enzymes are H3K4 specific histone demethylases involved in transcriptional regulation and DNA repair.1 These proteins are overexpressed in different kinds of cancer, including breast, prostate and bladder carcinomas, with positive effects on cancer proliferation and chemoresistance.2,3 For these reasons, these enzymes are potential therapeutic targets. In the present study, we analyzed the effects of three different inhibitors of KDM5 enzymes in MCF-7 breast cancer cells over-expressing one of them, namely KDM5B/JARID1B.4 In particular, compounds RS3195, RS3152, RS3183, RS5033 and RS4995 were assayed in terms of H3K4 demethylation (western blot), radio-sensitivity (cytoxicity and clonogenic assays) and damage accumulation (COMET assay and kinetics of H2AX phosphorylation) (Figure 1). We showed that three compounds can selectively inhibit KDM5 enzymes and are capable of increasing sensitivity of breast cancer cells to ionizing radiation and radiation-induced damage. These findings confirmed the involvement of H3K4 specific demethylases in the response to DNA damage, showed a requirement of the catalytic function and suggested new strategies for the therapeutic use of their inhibitors. References 1. Blair, L. P.; Cao, J.; Zou, M. R.; Sayegh, J.; Yan, Q. Cancers 2011, 3, 1383–1404. 2. Xiang, Y.; Zhu, Z.; Han, G.; Ye, X.; Xu, B.; Peng, Z.; Ma, Y.; Yu, Y.; Lin, H.; Chen, A. P.; Chen, C. D. Proc. Natl. Acad. Sci. USA 2007, 104, 19226–19231. 3. Zeng, J.; Ge, Z.; Wang, L.; Li, Q.; Wang, N.; Bjorkholm, M.; Jia, J.; Xu, D. Gastroenterology 2010, 138, 981–992. 4. Pippa, S.; Mannironi, C.; Licursi, V.; Bombardi, L.; Colotti, G.; Cundari, E.; Mollica, A.; Coluccia, A.; Naccarato, V.; La Regina, G.; Silvestri, R.; Negri, R. Molecules 2019, 24, e1739.
Design, synthesis and biological evaluation of PDZ1 targeting NHERF1 inhibitors as anticancer agents / La Regina, G.; Naccarato, V.; Masci, D.; Puxeddu, M.; Bufano, M.; Nalli, M.; Coluccia, A.; Orlando, V.; Canettieri, G.; Gianni, S.; Silvestri, R.. - (2019), pp. 178-178. (Intervento presentato al convegno XXVI National Meeting in Medicinal Chemistry - XII Young Medicinal Chemists’ Symposium tenutosi a Milano).
Design, synthesis and biological evaluation of PDZ1 targeting NHERF1 inhibitors as anticancer agents
La Regina, G.;Naccarato, V.;Masci, D.;Bufano, M.;Nalli, M.;Coluccia, A.;Orlando, V.;Canettieri, G.;Gianni, S.;Silvestri, R.
2019
Abstract
KDM5 enzymes are H3K4 specific histone demethylases involved in transcriptional regulation and DNA repair.1 These proteins are overexpressed in different kinds of cancer, including breast, prostate and bladder carcinomas, with positive effects on cancer proliferation and chemoresistance.2,3 For these reasons, these enzymes are potential therapeutic targets. In the present study, we analyzed the effects of three different inhibitors of KDM5 enzymes in MCF-7 breast cancer cells over-expressing one of them, namely KDM5B/JARID1B.4 In particular, compounds RS3195, RS3152, RS3183, RS5033 and RS4995 were assayed in terms of H3K4 demethylation (western blot), radio-sensitivity (cytoxicity and clonogenic assays) and damage accumulation (COMET assay and kinetics of H2AX phosphorylation) (Figure 1). We showed that three compounds can selectively inhibit KDM5 enzymes and are capable of increasing sensitivity of breast cancer cells to ionizing radiation and radiation-induced damage. These findings confirmed the involvement of H3K4 specific demethylases in the response to DNA damage, showed a requirement of the catalytic function and suggested new strategies for the therapeutic use of their inhibitors. References 1. Blair, L. P.; Cao, J.; Zou, M. R.; Sayegh, J.; Yan, Q. Cancers 2011, 3, 1383–1404. 2. Xiang, Y.; Zhu, Z.; Han, G.; Ye, X.; Xu, B.; Peng, Z.; Ma, Y.; Yu, Y.; Lin, H.; Chen, A. P.; Chen, C. D. Proc. Natl. Acad. Sci. USA 2007, 104, 19226–19231. 3. Zeng, J.; Ge, Z.; Wang, L.; Li, Q.; Wang, N.; Bjorkholm, M.; Jia, J.; Xu, D. Gastroenterology 2010, 138, 981–992. 4. Pippa, S.; Mannironi, C.; Licursi, V.; Bombardi, L.; Colotti, G.; Cundari, E.; Mollica, A.; Coluccia, A.; Naccarato, V.; La Regina, G.; Silvestri, R.; Negri, R. Molecules 2019, 24, e1739.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
