AZD 7986

AZD 7986 is a reversible and covalent inhibitor of dipeptidyl peptidase 1 (DPP-1), also known as cathepsin C (IC₅₀ = 3.9 nM).^1,2 It is selective for DPP-1 over cathepsins S, -L, -B, -K, -D, -E, -Z, -H, and -G (IC₅₀s = >20 µM for all), as well as a panel of greater than 200 enzymes, receptors, ion channels, and transporters. AZD 7986 inhibits activation of the DPP-1 targets neutrophil elastase, proteinase 3, and cathepsin G in human bone marrow-derived CD34⁺ neutrophil progenitor cells (IC₅₀s = 61.7, 208.9, and 114.8 nM, respectively). Ex vivo, AZD 7986 (0.2, 2, and 20 mg/kg) inhibits activation of neutrophil elastase and proteinase 3 in rat bone marrow lysates. AZD 7986 suppresses the formation of pulmonary and circulating neutrophil extracellular traps (NETs), increases survival, and reduces the number of lung metastases in a 4T1 murine mammary carcinoma model.³

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1. Doyle, K., Lönn, H., Käck, H., et al. Discovery of second generation reversible covalent DPP1 inhibitors leading to an oxazepane amidoacetonitrile based clinical candidate (AZD7986). J. Med. Chem. 59(20), 9457-9472 (2016).

2. Korkmaz, B., Lesner, A., Marchand-Adam, S., et al. Lung protection by cathepsin C inhibition: A new hope for COVID-19 and ARDS? J. Med. Chem. 63(22), 13258-13265 (2020).

3. Xiao, Y., Cong, M., Li, J., et al. Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation. Cancer Cell 39(3), 423-437 (2021).