I would use KH-CB19 with caution; the profile of this compound needs to be developed further. The compound inhibits multiple CLKs (CLK1&3 - although it is somewhat selective for CLK1 over CLK3 in vitro). The compound also inhibits the related kinase DYRK1. KH-CB19 was active in cells but at signifiantly higher concentrations than in the enzymatic assay. I would like to see the compound screened against the full kinome to assess kinase selectivity more thoroughly. I would also like to see it screened against the recommended off-target panel of GPCRs, ion-channels, transporters, etc.
Users should also be mindful of the chemical structure of KH-CB19. For example, if the double bond in KH-CB19 isomerizes, it may form 4-cyanoBauerine C (compound 3 in the authors' manuscript). No data has been presented on the stability of KH-CB19 under biological conditions, so this transformation cannot be ruled out in a cellular or in vivo setting. KH-CB19 also contains an ester that can possibly hydrolyze to an acid. Such hydrolysis could happen in vivo or in cells in the presence of intracellular esterases. It may be that the two ortho-substituents retard any ester hydrolysis; however, in the absense of data related to this transformation, it remains a possibility. It would be interesting to see if the acid counterpart to KH-CB19 has any relevant activity; if not, it could serve as a negative control.
10 Jan 2017 )