AZD8154
Preclinical pharmacology
PI3K enzyme inhibition data
| Human | Dog | |||||
| pIC50 | IC50 nM | pIC50 | IC50 nM | pIC50 | IC50 nM | |
| PI3Kγ | 9.1 | 0.79 | 8.5 | 3.0 | 8.0 | 9.5 |
| PI3Kδ | 9.2 | 0.69 | 8.5 | 3.4 | 8.6 | 2.7 |
| PI3Kα | 7.2 | 61 | 7.5 | 30 | 7.8 | 15 |
| PI3Kβ | 5.9 | 1400 | 6.5 | 301 | 5.6 | 2600 |
In vitro inhibition of PI3K isoforms
| Cell line | pIC50 | IC50 nM | |
| PI3Kγ | RAW 264 | 9.1 | 0.76 |
| PI3Kδ | JEKO-1 | 8.4 | 4.3 |
| PI3Kα | PDPK1 | <4.7 | >18400 |
| PI3Kβ | TOR7 | <4.5 | >30000 |
In an in vivo rat inhaled LPS model, AZD8154 reduced BALf neutrophil recruitment with 83% inhibition at 0.3 mg/kg, 51% inhibition at 0.1 mg/kg, mild/no inhibition at 0.02 mg/kg. Inhaled AZD8154 dose-dependently inhibited the effects of inhaled ovalbumin challenge in sensitised rats, demonstrated by inhibition of phosphorylation of S6 ribosomal protein, cytokine release (IL-13, IL-17) and eosinophil influx at doses of 69 to 1180 μg/kg.
In studies using tissue derived from severe asthmatics AZD8154 dose dependently inhibited the release of cytokines from PBMCs stimulated with anti CD2, 3 & 28 and the expression of CD11b on the surface of eosinophils stimulated with eotaxin-3 and neutrophils stimulated with IL-8.
Safety and tolerability
AZD8154 was generally well tolerated with doses of 15-20 mg/kg/day being tolerated in preclinical studies of 2 to 4 weeks. However, across the range of studies, some rats (~ 2-3% in any affected group) exhibited poor condition which was considered to be secondary to gastrointestinal inflammation that was seen microscopically. This observed effect lacked any association with dose or study duration. In a small number of animals, at higher, longer-term dosing, inflammation was observed in other tissues (most notably affecting the skin). These effects are considered to be associated with PI3K inhibition.
Preclinical species showed an accumulation of alveolar macrophages in association with inflammation in the lungs. The NOEL for this effect in the 3-month studies was 603 ug/kg/day (rat) and 56.4 ug/kg/day (monkey). Although a pharmacological driver for this effect cannot be excluded, these findings are proposed to be related to the low solubility of AZD8154.
Clinical pharmacology
AZD8154 has been studied in a Phase-1 clinical study investigating the safety, tolerability and pharmacokinetics (PK) of AZD8154 in healthy human volunteers. AZD8154 demonstrated an acceptable safety profile, with no reports of serious adverse events or clinically significant drug-associated safety concerns. AZD8154 demonstrated prolonged lung retention and a half-life supporting once-daily dosing.
Suitable for and exclusions
Suitable for in-vitro experiments however AZD8154 should not be used in pre-clinical in-vivo or clinical studies.
Mechanism of Action
PI3Kgamma delta inhibitor
Original Therapeutic Area
Respiratory & Immunology
CNS Penetrant
Low
Route of administration
Topical (Inhaled)
Modality
Small Molecule
Additional Information
1. Sadiq MW., et al., (2021).
Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective PI3Kγδ dual inhibitor targeting airway inflammatory disease. Br J Clin Pharmacol. Jun 28. doi: 10.1111/bcp.14956. Epub ahead of print. PMID: 34182611.
2. Perry MWD., et al., (2021)
Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma. J Med Chem. Jun 24;64(12):8053-8075. doi: 10.1021/acs.jmedchem.1c00434. Jun 3. PMID: 34080862.
