Wednesday, November 25, 2015

Drugs in Clinical Pipeline: GSK143

GSK143 [2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide] is a potent and highly selective spleen tyrosine kinase (SYK) inhibitor (pIC50 = 7.5) showing good efficacy in the rat Arthus model. The selectivity profile of GSK143 was determined against a panel of 66 protein kinases and none were inhibited within 10-fold of SYK activity. GSK143 is greater than 600-fold selective for SYK over ZAP-70 (pIC50 = 4.7), the other member of the SYK kinase family [1].

The activity of GSK143 is as follows:

pIC50(SYK enzyme assay) = 7.5
pIC50(ZAP-70 enzyme assay) = 4.7
pIC50(LCK enzyme assay) = 5.3
pIC50(LYN enzyme assay) = 5.4
pIC50(JAK1 enzyme assay) = 5.8
pIC50(JAK2 enzyme assay) = 5.8
pIC50(JAK3 enzyme assay) = 5.7
pIC50(AURKB enzyme assay) = 4.8

Common Name: GSK143
Synonyms: GSK143; GSK-143; GSK 143
IUPAC Name: 
CAS Number: 1240390-27-5
Mechanism of Action: Kinase Inhibitor; SYK Inhibitor; Spleen Kinase Inhibitor
Indication: Various Cancers; Anti-inflammatory Drugs
Development Stage: Investigational

Company: GlaxoSmithKline

The progression of GSK143 was terminated due to a mutagenicity risk highlighted in the Ames assay, it remains one of the most selective SYK inhibitors disclosed to date and hence an excellent tool molecule for further evaluation of the SYK mechanism.

1. Liddle, J.; et. al. Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor. Bioorg Med Chem Lett 2011, 21(20), 6188-6194.