TY - JOUR
T1 - Rad51/BRCA2 disruptors inhibit homologous recombination and synergize with olaparib in pancreatic cancer cells
AU - Roberti, Marinella
AU - Schipani, Fabrizio
AU - Bagnolini, Greta
AU - Milano, Domenico
AU - Giacomini, Elisa
AU - Falchi, Federico
AU - Balboni, Andrea
AU - Manerba, Marcella
AU - Farabegoli, Fulvia
AU - De Franco, Francesca
AU - Robertson, Janet
AU - Minucci, Saverio
AU - Pallavicini, Isabella
AU - Di Stefano, Giuseppina
AU - Girotto, Stefania
AU - Pellicciari, Roberto
AU - Cavalli, Andrea
PY - 2019/3/1
Y1 - 2019/3/1
N2 - Olaparib is a PARP inhibitor (PARPi). For patients bearing BRCA1 or BRCA2 mutations, olaparib is approved to treat ovarian cancer and in clinical trials to treat breast and pancreatic cancers. In BRCA2-defective patients, PARPi inhibits DNA single-strand break repair, while BRCA2 mutations hamper double-strand break repair. Recently, we identified a series of triazole derivatives that mimic BRCA2 mutations by disrupting the Rad51-BRCA2 interaction and thus double-strand break repair. Here, we have computationally designed, synthesized, and tested over 40 novel derivatives. Additionally, we designed and conducted novel biological assays to characterize how they disrupt the Rad51-BRCA2 interaction and inhibit double-strand break repair. These compounds synergized with olaparib to target pancreatic cancer cells with functional BRCA2. This supports the idea that small organic molecules can mimic genetic mutations to improve the profile of anticancer drugs for precision medicine. Moreover, this paradigm could be exploited in other genetic pathways to discover innovative anticancer targets and drug candidates.
AB - Olaparib is a PARP inhibitor (PARPi). For patients bearing BRCA1 or BRCA2 mutations, olaparib is approved to treat ovarian cancer and in clinical trials to treat breast and pancreatic cancers. In BRCA2-defective patients, PARPi inhibits DNA single-strand break repair, while BRCA2 mutations hamper double-strand break repair. Recently, we identified a series of triazole derivatives that mimic BRCA2 mutations by disrupting the Rad51-BRCA2 interaction and thus double-strand break repair. Here, we have computationally designed, synthesized, and tested over 40 novel derivatives. Additionally, we designed and conducted novel biological assays to characterize how they disrupt the Rad51-BRCA2 interaction and inhibit double-strand break repair. These compounds synergized with olaparib to target pancreatic cancer cells with functional BRCA2. This supports the idea that small organic molecules can mimic genetic mutations to improve the profile of anticancer drugs for precision medicine. Moreover, this paradigm could be exploited in other genetic pathways to discover innovative anticancer targets and drug candidates.
KW - Anticancer drugs
KW - Homologous recombination
KW - PARP inhibitors
KW - Protein-protein small molecule inhibitors
KW - Synthetic lethality
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U2 - 10.1016/j.ejmech.2019.01.008
DO - 10.1016/j.ejmech.2019.01.008
M3 - Article
C2 - 30660828
AN - SCOPUS:85060093491
VL - 165
SP - 80
EP - 92
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -