Phosphatidyl inositol 3 kinases (PI3Ks) are a family of enzymes that phosphorylate the 3’-hydroxyl of the membrane lipid phosphatidyl inositol and are responsible for initiating a series of downstream cascades in multiple cell types. The PI3Kγ and δ isoforms are predominantly found in leukocytes; inhibition of one or both has been shown in both pre-clinical and clinical studies to provide powerful and selective immune modulation in cancer and respiratory diseases. We have previously described the discovery of a series of highly selective PI3Kγ inhibitors from a screening hit. Through multiple structural changes to this series we were able to increase the inhibition of PI3Kδ leading to the discovery of molecules with a dual inhibition profile. Further optimisation of the structures to ensure good retention in lung led to the identification of AZD8154 as a highly potent and selective dual PI3Kγδ inhibitor with properties suitable for inhaled dosing. Studies using human PBMCs from asthmatic patients showed a synergistic advantage of inhibition of both PI3Kγ and δ over inhibition of a single isoform in modulation of cytokine release. In vivo studies in a rat ovalbumin challenge model of allergic asthma showed target engagement through inhibition of the phosphorylation of S6 ribosomal protein, inhibition of the release of key cytokines (IL-5, IL-13, IL-17) and inhibition of the influx of eosinophils, lymphocytes and neutrophils into the lung as measured in BAL. These effects were long-lasting with inhibition still significant from a challenge 7h after dosing. AZD8154 is currently undergoing Phase 1 clinical studies (NCT03436316); details of the initial human PK will be shown.

Discovery of AZD8154, a dual PI3Kγδ inhibitor, as an inhaled treatment for asthma

ACS Fall 2020 Virtual Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.