Forsyth and coworkers present in the given reference the development of an aminopyrimidine based JAK2 inhibitor. Comprehensive SAR and characterization via enzymatic and cellular assays is given throughout the development story. The Probe candidate XL019 was also co-crystallized with the target and shows an interesting DFG-motif interaction with the terminal amide residue. This compound was also more intensively investigated concerning its selectivity, PK- and PD-profile.
However, the cellular activity (IC50 386nM) as well as selectivity (ca. 2-fold) for JAK2 is not as pronounced as in the biochemical assay on the isolated enzyme. Moreover, most probably due to its generic amino pyrimidine scaffold it shows moderate off target activities in a relatively small kinase panel (most prominent JAK1, FLT3, c-KIT and PDGFRB with 130 to 230 nM).
The in vivo characterization of this probe candidate is still noteworthy and it may serve as a valuable in vivo tool, but first the on- and off-target activities should be further investigated in cellular models to get a clear estimation of a valid dosage regiment without risking off-target effects.
26 Feb 2021 )