Saturday, November 28, 2015

Drugs in Clinical Pipeline: RO-9021

RO-9021 [(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide] is an oral, ATP-competative and selective inhibitor of spleen tyrosine kinase (SYK). RO-9021 potently inhibited SYK kinase activity with an average IC50 of 5.6 nM. Selectivity of RO-9021 against a panel of 451 wild-type and mutant protein kinases was assessed using an ATP binding site competition assay developed by KINOMEscan Inc.  

RO-9021 is a highly selective SYK inhibitor with low S-scores of 0.003 for S(99) and 0.015 for S(90), indicating that SYK is the only kinase with 99% competition with RO-9021 (1 uM) in a total of 392 tested kinases. There were only a total of seven kinases (JAK1, JAK3, GCN2, SLK, FLT3(ITD), PAK2) including SYK, having more than 90% competition with RO9021. It inhibited JAK1 and JAK3 with 97% at 1 uM.

1. Liao, C.; et. al. Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: implications for SYK inhibitors in autoimmune disease therapy. Arthritis Res Ther 2013, 15(5), R146.