A cdk1 inhibitor Cell Cycle inhibitor Lure

These interactions mimic hydrogen bonds identified inside the crystal construction of Jak3 with AFN941. A different major interaction includes hydrogen bonds formed amongst the nitrile function and Arg953 at the opening in the cleft.

Comparing the cdk1 inhibitor docking poses for 1, 2, 3 and 4 found in the highest scoring Jak3 docking complexes to the minimum energy structures of the unbound 1, 2, 3 and 4 from the conformational analyses provides valuable insight into the superior binding associated with the stereochemical configuration of 1. Figure 6 shows the predicted unbound conformation for each compound overlaid Cell Cycle inhibitor with the conformation associated with docking at Jak3. From this rendering, it is clear that only 1 docks with Jak3 in a conformation that extensively resembles the compounds minimum energy conformation. For 2, the six member ring assumes a half chair conformation with both the substituent in equatorial position.

23 Conversely, Jak2 is ubiquitously expressed and knockouts are embryonic lethal. Cell Cycle inhibitor 24 Given these data, substantial effort has been invested in the search for highly selective Jak3 inhibitors. Jak2 possesses a high degree of homology to Jak3 and is particularly homologous at the kinase active site. 19 Comparison between the catalytic pockets of crystal structures of Jak3 and Jak2 revealed conformational differences in the glycine rich loop and the activation loop that result in a rather tighter pocket for Jak2. Docking of 1 within the crystal structure of the catalytic cleft of Jak225 suggests that the complexes of 1 with both Jak3 and Jak2 are decidedly similar.

The IC50 values reported by Changelian et al. indicate a small degree of selectivity between Jak3 and Jak2.