Tuesday, November 10, 2015

Drugs in Clinical Pipeline: GSK-2269557 | Treatment of COPD | Treatment of Asthma | Treatment of Autoimmune Diseases I PIK3d Inhibitor

GSK-2269557 [2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole] is a potent, selective nanomolar inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA phosphoinositide-3 kinases (PI3K). GSK-2269557 is more selective for PI3Kδ relative to other PI3K class I enzymes (pKi: PI3Kδ = 9.9) with greater than 1000-fold selectivity over PI3Kα, PI3Kγ and PI3Kβ. It has a pIC50 value greater than 7, with at least ten-fold selectivity for PI3Kδ over PI3Kα, PI3Kγ and PI3Kβ [1, 2].

GSK-2269557: 2D and 3D Structure

GSK-2269557 and GSK-2292767 are designed especially for the treatment of respiratory indications via inhalation. Both the drugs meet the criteria necessary for compounds to be delivered as aerosolized dry powder formulations. The advantages of delivering such inhibitors by this route are that it can minimize the risk of systemic, mechanism-related side effects and it also facilitates exploring combinations of the PI3Kδ inhibitors with other anti-asthma agents such as the corticosteroids [3]. 

GSK-2269557 is currently in Phase 2 clinical trials for chronic obstructive pulmonary disease (COPD) and asthma.

The activity of GSK-2269557 is as follows:

pIC50 (PI3Kδ enzyme assay) = greater than 7
pKi (PI3Kδ enzyme assay) = 9.9

Common Name: GSK-2269557
Synonyms: GSK-2269557; GSK2269557; GSK 2269557
IUPAC Name: 2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole
CAS Number: 1254036-71-9; 1254036-77-5 (hydrochloride)
Mechanism of Action: Kinase Inhibitor; PI3K Inhibitor; PI3K delta Inhibitor
Indication: Treatment of COPD; Treatment of Asthma; Treatment of Autoimmune Diseases
Development Stage: Phase II
Company: GlaxoSmithKline

1H NMR (Estimated) for GSK-2269557

1. Hamblin, J. N.; et. al. Oxazole substituted indazoles as pi3-kinase inhibitors. WO2010125082A1
2. Down, K.; et. al. Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase d for the Treatment of Respiratory Disease. J Med Chem 2015, 58(18), 7381-7399.
3. Norman, P. Evaluation of WO2012032067 and WO2012055846: two selective PI3Kd inhibitors, which is GSK-2269557? Expert Opin Ther Pat 2012, 22(8), 965-970.