Discovery of ART5537: A Potent and Selective Small-Molecule Probe for EXO1
Sam E Mann1, Owen A Davis1, Jörg Bomke2
1Artios Pharma Ltd., B940, Babraham Research Campus, Cambridge CB22 3FH, U.K.
Abstract:
Exonuclease 1 (EXO1) is emerging as a target of interest in oncology due to its involvement in multifaceted DNA metabolic processes, particularly in homologous recombination (HR). Evidence is building that BRCA1-deficient cancers are sensitive to loss of EXO1, suggesting therapeutic potential for treating certain subsets of patients. However, EXO1 remains under-explored, with very few reported inhibitors, and there is a paucity of good quality, potent, and selective pharmacological tools to explore its biology. Here, we describe a metal-chelating fragment screen, which resulted in highly selective, submicromolar EXO1 hits. Our subsequent structure-based design and optimization led to the discovery of ART5537, the first highly potent and selective EXO1 inhibitor. We demonstrate that inhibition of EXO1 leads to potent suppression of HR in cells and that the HR inhibition of ART5537 is driven exclusively by EXO1. Furthermore, we show that ART5537 sensitizes cancer cells to ionizing radiation (IR) and synergizes with PARP inhibitors (PARPi).
Insights
Researchers developed ART5537, a potent and selective inhibitor of Exonuclease 1 (EXO1). This discovery offers a new tool to explore EXO1
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Exonuclease 1 (EXO1) plays a key role in DNA repair pathways like homologous recombination (HR).
- BRCA1-deficient cancers show sensitivity to EXO1 loss, highlighting its therapeutic potential.
- Limited availability of potent and selective EXO1 inhibitors hinders biological exploration.
Purpose of the Study:
- To identify and develop novel, potent, and selective inhibitors of Exonuclease 1 (EXO1).
- To investigate the role of EXO1 inhibition in homologous recombination (HR) and cancer cell sensitivity.
Main Methods:
- A metal-chelating fragment screen was employed to identify initial EXO1 inhibitors.
- Structure-based drug design and optimization were used to discover ART5537.
- Cellular assays were performed to assess HR suppression, EXO1 dependency, and drug synergy.
Main Results:
- Discovery of ART5537, the first highly potent and selective EXO1 inhibitor.
- ART5537 effectively suppresses homologous recombination (HR) in a manner exclusively dependent on EXO1.
- ART5537 sensitizes cancer cells to ionizing radiation (IR) and demonstrates synergy with PARP inhibitors (PARPi).
Conclusions:
- ART5537 represents a significant advancement in pharmacological tools for studying EXO1.
- Targeting EXO1 with ART5537 shows promise for sensitizing cancer cells to existing therapies like IR and PARPi.
- This work opens new avenues for developing targeted therapies for BRCA1-deficient cancers and other malignancies involving DNA repair defects.
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