TY - JOUR
T1 - Synthetic Lethality in Pancreatic Cancer
T2 - Discovery of a New RAD51-BRCA2 Small Molecule Disruptor That Inhibits Homologous Recombination and Synergizes with Olaparib
AU - Bagnolini, Greta
AU - Milano, Domenico
AU - Manerba, Marcella
AU - Schipani, Fabrizio
AU - Ortega, Jose Antonio
AU - Gioia, Dario
AU - Falchi, Federico
AU - Balboni, Andrea
AU - Farabegoli, Fulvia
AU - De Franco, Francesca
AU - Robertson, Janet
AU - Pellicciari, Roberto
AU - Pallavicini, Isabella
AU - Peri, Sebastiano
AU - Minucci, Saverio
AU - Girotto, Stefania
AU - Di Stefano, Giuseppina
AU - Roberti, Marinella
AU - Cavalli, Andrea
N1 - Funding Information:
This work was supported by the Associazione Italiana per la Ricerca sul Cancro AIRC (Progetto IG 2018, id 21386), the Italian Institute of Technology (IIT), and the University of Bologna. We thank Prof. Maurizio Recanatini for fruitful discussions.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/3/12
Y1 - 2020/3/12
N2 - Synthetic lethality is an innovative framework for discovering novel anticancer drug candidates. One example is the use of PARP inhibitors (PARPi) in oncology patients with BRCA mutations. Here, we exploit a new paradigm based on the possibility of triggering synthetic lethality using only small organic molecules (dubbed "fully small-molecule-induced synthetic lethality"). We exploited this paradigm to target pancreatic cancer, one of the major unmet needs in oncology. We discovered a dihydroquinolone pyrazoline-based molecule (35d) that disrupts the RAD51-BRCA2 protein-protein interaction, thus mimicking the effect of BRCA2 mutation. 35d inhibits the homologous recombination in a human pancreatic adenocarcinoma cell line. In addition, it synergizes with olaparib (a PARPi) to trigger synthetic lethality. This strategy aims to widen the use of PARPi in BRCA-competent and olaparib-resistant cancers, making fully small-molecule-induced synthetic lethality an innovative approach toward unmet oncological needs.
AB - Synthetic lethality is an innovative framework for discovering novel anticancer drug candidates. One example is the use of PARP inhibitors (PARPi) in oncology patients with BRCA mutations. Here, we exploit a new paradigm based on the possibility of triggering synthetic lethality using only small organic molecules (dubbed "fully small-molecule-induced synthetic lethality"). We exploited this paradigm to target pancreatic cancer, one of the major unmet needs in oncology. We discovered a dihydroquinolone pyrazoline-based molecule (35d) that disrupts the RAD51-BRCA2 protein-protein interaction, thus mimicking the effect of BRCA2 mutation. 35d inhibits the homologous recombination in a human pancreatic adenocarcinoma cell line. In addition, it synergizes with olaparib (a PARPi) to trigger synthetic lethality. This strategy aims to widen the use of PARPi in BRCA-competent and olaparib-resistant cancers, making fully small-molecule-induced synthetic lethality an innovative approach toward unmet oncological needs.
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U2 - 10.1021/acs.jmedchem.9b01526
DO - 10.1021/acs.jmedchem.9b01526
M3 - Article
C2 - 32037829
AN - SCOPUS:85081944614
VL - 63
SP - 2588
EP - 2619
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 5
ER -