Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550).
Here, we examine the significance that stereochemistry plays within the clinically relevant Janus kinase 3 (Jak3) inhibitor 1 (CP-690,550). A synthesis of all four enantiopure stereoisomers of the drug was carried out and an examination of each compound revealed that only the enantiopure 3R,4R isomer was capable of blocking Stat5 phosphorylation (Jak3 dependent). Each compound was profiled across a panel of over 350 kinases, which revealed a high level of selectivity for the Jak family kinases for these related compounds. Each stereoisomer retained a degree of binding to Jak3 and Jak2 and the 3R,4S and 3S,4R stereoisomers were further revealed to have binding affinity for selected members of the STE7 and STE20 subfamily of kinases. Finally, an appraisal of the minimum energy conformation of each stereoisomer and molecular docking at Jak3 was performed in an effort to better understand each compounds selectivity and potency profiles.
Jiang
Jian-kang
JK
NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
Ghoreschi
Kamran
K
Deflorian
Francesca
F
Chen
Zhi
Z
Perreira
Melissa
M
Pesu
Marko
M
Smith
Jeremy
J
Nguyen
Dac-Trung
DT
Liu
Eric H
EH
Leister
William
W
Costanzi
Stefano
S
O'Shea
John J
JJ
Thomas
Craig J
CJ
D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D053614:Janus Kinase 2 / Q000737:chemistry; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D009010:Monte Carlo Method; D010880:Piperidines; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism
D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; C507924:JAK2 protein, human; D053614:Janus Kinase 2