3-Cyano-6-(5-methyl-3-pyrazoloamino) pyridines (Part 2): A dual inhibitor of Aurora kinase and tubulin polymerization

Compound 3g exhibited Aurora kinase inhibition, excellent protein kinase selectivity to other 66 kinases, inhibition of phosphorylation of Ser10 of histon H3 as an Aurora kinase inhibitor, and inhibition tubulin polymerization in vitro, good cell membrane permeability, and good PK profile. Therefore compound 3g was effective in some antitumor mouse models at a dose of 30mg/kgpoqd. [Display omitted] A new class of a dual inhibitor of Aurora kinase and tubulin polymerization was created by introducing various substituted phenoxyethylamino or pyridyloxyethylamino groups to the 2-position of 3-cyano-4-methyl-6-(5-methyl-3-pyrazoloamino)-pyridine. Compound 3g exhibited Aurora kinase inhibition, excellent protein kinase selectivity to Aurora kinase in comparison with 66 other kinases, inhibition of phosphorylation of Ser10 of histone H3 as an Aurora kinase inhibitor, inhibition of tubulin polymerization in vitro, good cell membrane permeability, and a good PK profile. Therefore compound 3g was effective in some antitumor mouse models at a dose of 30mg/kgpoqd.