Source: International Congress 2014 – New treatments for cough, asthma, COPD and ILDs
Disease area: Airway diseases

Abstract

Rationale: PI3Kd is a lipid kinase involved in the activation, proliferation and differentiation of leukocytes and thus is an anti-inflammatory target for the treatment of asthma and COPD.Aim: to characterize the enzymatic and cellular potency and selectivity of LAS194223.Methods: PI3Ka, PI3Kb, PI3Kd, PI3Kg enzymatic activities were assessed by HTRF kinase assays. Cellular potency was assessed in different relevant cell types: inhibition of phospho- AKT induced by M-CSF in THP-1 cells, inhibition of fMLP induced ROS production in PMN, and inhibition of CD3 induced IFNg in PBMC. PI3Kb cellular potency was determined in HUVEC cells through inhibition of S1P induced phosphoAKT. The selectivity profile was assessed at 1 mM in a Millipore KinaseProfiler panel (Millipore), CEREP Express profile panel (CEREP) and in a lipid kinase panel (ProQinase) comprising a total of 114 target proteins.Results: LAS194223 potently inhibits PI3Kd kinase activity (IC₅₀0.1 nM) and shows a fold ratio of 137, 10 and 4 for PI3Ka, PI3Kb and PI3Kg respectively. LAS194223 was also potent in cellular assays including M-CSF induced pAKT in THP-1 (IC50 1.6 nM), fMLP induced ROS production in PMN (IC50 18nM) and CD3 induced IFNg in PBMC (IC50 4 nM). No relevant off-target activities were identified. Cellular potency for PI3Kb isoform in HUVEC cells shows a 260 fold vs PI3Kd in THP-1 assay.Conclusions: LAS194223 is a potent, non-cytotoxic compound, with good selectivity vs PI3Ka and PI3Kb isoforms that shows activity also in PI3Kg. These promising in vitro results prompted us to further characterize its ADME profile and in vivo efficacy by inhaled route.

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M. Calbet, M. Lehner, M. Bravo, J. Cabedo, S. Paris, S. Soria, M. Erra, M. Miralpeix (Sant Feliu del Llobregat, Spain). In vitro characterization of a novel inhaled PI3Kd inhibitor LAS194223. Eur Respir J 2014; 44: Suppl. 58, 1506

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