Abstract
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.
Highlights
Synthetic lethality is a new opportunity for discovering new anticancer molecules for personalized targeted therapies
poly (ADPribose)polymerase (PARP) is crucial for repairing DNA single-strand breaks (SSBs), whereas BRCA1/2 are important for repairing DNA double-strand breaks (DSBs) by homologous recombination (HR)
The other pocket can lodge the BRC4’s LFDE motif far from the oligomerization interface (Figure 2).[24,33−35] Recently, we ran a successful virtual screening campaign based on high-throughput docking at the FxxA pocket to identify the first RAD51-BRCA2 disruptors.[30]
Summary
Synthetic lethality is a new opportunity for discovering new anticancer molecules for personalized targeted therapies. Small organic molecules can target the synthetically lethal partner of an altered gene in cancer cells but not in normal cells. This creates opportunities to selectively kill cancer cells while sparing normal cells.[6−12]. Cancer cells with defects in one DDR pathway can become reliant on other pathways for their survival Targeting these other DDR pathways can potentially cause selective cancer cell death through synthetic lethality. In 2014, olaparib was the first PARP inhibitor (PARPi) approved to treat advanced ovarian cancer associated with defective BRCA genes.[17] In 2018, olaparib was approved to treat metastatic breast tumors associated with germline BRCA mutations.[18] In 2019, olaparib gained the FDA approval as first-line maintenance treatment of germline BRCA-mutated metastatic
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