JAK3 vs. JAK2 at 20 μM, but inhibitory potencies were only assigned to a single
structure (31). This compound showed a time-dependent IC 50 value of 40 nM and
7 nM after 20 min and 90 min preincubation, respectively. Although the covalent
binding mode was not unambiguously confirmed by experimental data in this patent,
Goedken et al. later reported the X-ray crystal structure of close analog 32 covalently
bound to JAK3 (Fig. 8) [41].
Two patents from Principia Biopharma published in 2012 and 2014 claimed JAK3
inhibitors based on a 5H-pyrrolo[2,3-b]pyrazine scaffold equipped with acrylamide or
Fig. 8 JAK3 in covalent complex with inhibitor 32 (PDB-code: 4QPS). Hydrogen bonds are
depicted as dashed yellow lines and water molecules as red spheres. The Met902 gatekeeper residue
is highlighted in the ball and stick representation
Fig. 9 Acrylamide- and α-cyanoacrylamide-derived JAK3 inhibitors from Principia Biopharma
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M. Gehringer and M. Forster
structure (31). This compound showed a time-dependent IC 50 value of 40 nM and
7 nM after 20 min and 90 min preincubation, respectively. Although the covalent
binding mode was not unambiguously confirmed by experimental data in this patent,
Goedken et al. later reported the X-ray crystal structure of close analog 32 covalently
bound to JAK3 (Fig. 8) [41].
Two patents from Principia Biopharma published in 2012 and 2014 claimed JAK3
inhibitors based on a 5H-pyrrolo[2,3-b]pyrazine scaffold equipped with acrylamide or
Fig. 8 JAK3 in covalent complex with inhibitor 32 (PDB-code: 4QPS). Hydrogen bonds are
depicted as dashed yellow lines and water molecules as red spheres. The Met902 gatekeeper residue
is highlighted in the ball and stick representation
Fig. 9 Acrylamide- and α-cyanoacrylamide-derived JAK3 inhibitors from Principia Biopharma
234
M. Gehringer and M. Forster