RAD51 family members play a central role in homologous recombination (HR) and DNA double strand breaks (DSBs) repair. In mammalian cells, BRCA2 is shown to regulate both the intracellular localization and DNA-binding ability of RAD51, leading to genomic instability and tumorigenesis if inactivated. Most recently BRCA mutations have been exploited to achieve tumor regression, applying the synthetic lethality paradigm with the use of PARP inhibitors (PARPi). Chemical disruption of protein-protein interactions (PPIs) between BRCA2 and RAD51 could mimic a state of ‘BRCAness’ and potentiate PARPi DNA damage-induced cell death through a fully small-molecule-induced synthetic lethality, particularly for difficult to treat cancers, as BRCA-competent and olaparib (PARPi) resistant pancreatic adenocarcinoma. We previously reported a dihydroquinolone pyrazoline-based RAD51-BRCA2 disruptor (ARN24089) that synergizes with olaparib to trigger synthetic lethality in BxPC3 cells (human primary pancreatic adenocarcinoma with fully functional BRCA2). Proteomics analysis was performed to understand if BRC4, the strongest natural RAD51 binder BRCA2 repeat, and ARN24089 treatment up and/or downregulated similar HR proteins, indication of a shared mechanism of action. Moreover, to better characterize ARN24089 biological mode of action, we investigated its activity, alone or in combination with olaparib, in pancreatic ductal adenocarcinoma (PDAC) organoids. Despite the promising results, ARN24089 presents translational hurdles due to its low solubility, low bioavailability, and formulation challenges, limiting its application in in vivo disease models. Parallel to new formulation strategies for the delivery of ARN24089 (e.g. nanocrystals), we have therefore initiated a medicinal chemistry campaign that has resulted in the synthesis of a large number of chemical compounds which physico-chemical and ADME properties have been assessed through several in-house assays. Through these translational approaches, we therefore aim at making fully small-molecule-induced synthetic lethality an effective and innovative approach toward unmet oncological needs.
Insights into the activity of ARN24089, a new RAD51-BRCA2 disruptor that inhibits homologous recombination and achieves synthetic lethality in pancreatic cancer / Previtali V., Myers S. H., Bagnolini G., Poppi L., Rinaldi F., Schipani F., Ortega J. A., De Franco F., Pellicciari R., Girotto S., Oliviero G., Walsh N., Valenti G., Tirelli N., Di Stefano G., Roberti M., Cavalli A.. - ELETTRONICO. - (2022), pp. 1-1. (Intervento presentato al convegno ACS Spring 2022 tenutosi a San Diego Convention Center, Room 16A nel 20/03/2023).
Insights into the activity of ARN24089, a new RAD51-BRCA2 disruptor that inhibits homologous recombination and achieves synthetic lethality in pancreatic cancer
Bagnolini G.;Poppi L.;Rinaldi F.;Di Stefano G.;Roberti M.;Cavalli A.
2022
Abstract
RAD51 family members play a central role in homologous recombination (HR) and DNA double strand breaks (DSBs) repair. In mammalian cells, BRCA2 is shown to regulate both the intracellular localization and DNA-binding ability of RAD51, leading to genomic instability and tumorigenesis if inactivated. Most recently BRCA mutations have been exploited to achieve tumor regression, applying the synthetic lethality paradigm with the use of PARP inhibitors (PARPi). Chemical disruption of protein-protein interactions (PPIs) between BRCA2 and RAD51 could mimic a state of ‘BRCAness’ and potentiate PARPi DNA damage-induced cell death through a fully small-molecule-induced synthetic lethality, particularly for difficult to treat cancers, as BRCA-competent and olaparib (PARPi) resistant pancreatic adenocarcinoma. We previously reported a dihydroquinolone pyrazoline-based RAD51-BRCA2 disruptor (ARN24089) that synergizes with olaparib to trigger synthetic lethality in BxPC3 cells (human primary pancreatic adenocarcinoma with fully functional BRCA2). Proteomics analysis was performed to understand if BRC4, the strongest natural RAD51 binder BRCA2 repeat, and ARN24089 treatment up and/or downregulated similar HR proteins, indication of a shared mechanism of action. Moreover, to better characterize ARN24089 biological mode of action, we investigated its activity, alone or in combination with olaparib, in pancreatic ductal adenocarcinoma (PDAC) organoids. Despite the promising results, ARN24089 presents translational hurdles due to its low solubility, low bioavailability, and formulation challenges, limiting its application in in vivo disease models. Parallel to new formulation strategies for the delivery of ARN24089 (e.g. nanocrystals), we have therefore initiated a medicinal chemistry campaign that has resulted in the synthesis of a large number of chemical compounds which physico-chemical and ADME properties have been assessed through several in-house assays. Through these translational approaches, we therefore aim at making fully small-molecule-induced synthetic lethality an effective and innovative approach toward unmet oncological needs.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
