Synthetic lethality is a lethal phenotype arising from the combination of two specific gene mutations, which are harmless when they occur individually (Fig.1) 1. Targeting a pair of synthetic lethal genes represents an attractive opportunity in pharmaceutical field for the development of novel therapeutics. One straightforward application of synthetic lethality in anticancer drug development is the treatment of BRCA2-defective oncology patients with Olaparib, the first approved PARP inhibitor. BRCA2 and PARP are proteins involved in two independent mechanisms of DNA repair, respectively homologous recombination (HR) and base excision repair (BER). Due to cancer cells genomic instability, the simultaneous impairment of both DNA repair pathways triggers the synthetic lethality. In this context, as a new anticancer drug discovery concept, we proposed to trigger a fully-small-molecule induced synthetic lethality combining Olaparib with a BRCA2-RAD51 protein-protein (PP) interaction disruptor that mimic BRCA2 mutation2. Targeting PP interactions is an attractive strategy for designing innovative drugs. However it was proven to be challenging due to the typical PP large and flat interfaces 3. In-depth studies of the target structures identified two PP critical “hotspots” on RAD51 surface, zone I and II, as suitable targets for the design of small molecule PP interaction inhibitors. Following a structure-based approach focused on zone I, a virtual screening campaign allowed us to identify potential triazole-based hit compounds. Compound 1 showed to inhibit BRCA2-RAD51 PP interaction in biochemical assay. To discover more effective compounds and depict general structure-activity relationship (SAR) studies, we synthesized a library of new triazole analogues (Fig.2). The compound 2 proved to increase the response to Olaparib in pancreatic cancer cells expressing a functional BRCA2. This supports the idea that small organic molecules can mimic genetic mutations. To promote sustainable chemistry, we privileged protocols that exploit microwave-assisted synthesis.
Bagnolini, G., Balboni, A., Manerba, M., Farabegoli, F., DI STEFANO, G., Roberti, M., et al. (2019). Design and synthesis of BRCA2-RAD51 disruptors to induce synthetic lethality in anticancer therapy.
Design and synthesis of BRCA2-RAD51 disruptors to induce synthetic lethality in anticancer therapy
Greta BagnoliniPrimo
;Andrea Balboni;Marcella Manerba;Fulvia Farabegoli;Giuseppina Di Stefano;Marinella Roberti;Andrea Cavalli
2019
Abstract
Synthetic lethality is a lethal phenotype arising from the combination of two specific gene mutations, which are harmless when they occur individually (Fig.1) 1. Targeting a pair of synthetic lethal genes represents an attractive opportunity in pharmaceutical field for the development of novel therapeutics. One straightforward application of synthetic lethality in anticancer drug development is the treatment of BRCA2-defective oncology patients with Olaparib, the first approved PARP inhibitor. BRCA2 and PARP are proteins involved in two independent mechanisms of DNA repair, respectively homologous recombination (HR) and base excision repair (BER). Due to cancer cells genomic instability, the simultaneous impairment of both DNA repair pathways triggers the synthetic lethality. In this context, as a new anticancer drug discovery concept, we proposed to trigger a fully-small-molecule induced synthetic lethality combining Olaparib with a BRCA2-RAD51 protein-protein (PP) interaction disruptor that mimic BRCA2 mutation2. Targeting PP interactions is an attractive strategy for designing innovative drugs. However it was proven to be challenging due to the typical PP large and flat interfaces 3. In-depth studies of the target structures identified two PP critical “hotspots” on RAD51 surface, zone I and II, as suitable targets for the design of small molecule PP interaction inhibitors. Following a structure-based approach focused on zone I, a virtual screening campaign allowed us to identify potential triazole-based hit compounds. Compound 1 showed to inhibit BRCA2-RAD51 PP interaction in biochemical assay. To discover more effective compounds and depict general structure-activity relationship (SAR) studies, we synthesized a library of new triazole analogues (Fig.2). The compound 2 proved to increase the response to Olaparib in pancreatic cancer cells expressing a functional BRCA2. This supports the idea that small organic molecules can mimic genetic mutations. To promote sustainable chemistry, we privileged protocols that exploit microwave-assisted synthesis.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
