TY - JOUR
T1 - Development of selective covalent Janus kinase 3 inhibitors
AU - Tan, Li
AU - Akahane, Koshi
AU - McNally, Randall
AU - Reyskens, Kathleen M. S. E.
AU - Ficarro, Scott B.
AU - Liu, Suhu
AU - Herter-Sprie, Grit S.
AU - Koyama, Shohei
AU - Pattison, Michael J.
AU - Labella, Katherine
AU - Johannessen, Liv
AU - Akbay, Esra A.
AU - Wong, Kwok Kin
AU - Frank, David A.
AU - Marto, Jarrod A.
AU - Look, Thomas A.
AU - Arthur, J. Simon C
AU - Eck, Michael J.
AU - Gray, Nathanael S.
PY - 2015/8/27
Y1 - 2015/8/27
N2 - The Janus kinases (JAKs) and their downstream effectors, signal transducer and activator of transcription proteins (STATs), form a critical immune cell signaling circuit, which is of fundamental importance in innate immunity, inflammation, and hematopoiesis, and dysregulation is frequently observed in immune disease and cancer. The high degree of structural conservation of the JAK ATP binding pockets has posed a considerable challenge to medicinal chemists seeking to develop highly selective inhibitors as pharmacological probes and as clinical drugs. Here we report the discovery and optimization of 2,4-substituted pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of structure-activity relationship (SAR) utilizing biochemical and transformed Ba/F3 cellular assays resulted in identification of potent and selective inhibitors such as compounds 9 and 45. A 2.9 Å cocrystal structure of JAK3 in complex with 9 confirms the covalent interaction. Compound 9 exhibited decent pharmacokinetic properties and is suitable for use in vivo. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology. (Chemical Equation Presented).
AB - The Janus kinases (JAKs) and their downstream effectors, signal transducer and activator of transcription proteins (STATs), form a critical immune cell signaling circuit, which is of fundamental importance in innate immunity, inflammation, and hematopoiesis, and dysregulation is frequently observed in immune disease and cancer. The high degree of structural conservation of the JAK ATP binding pockets has posed a considerable challenge to medicinal chemists seeking to develop highly selective inhibitors as pharmacological probes and as clinical drugs. Here we report the discovery and optimization of 2,4-substituted pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of structure-activity relationship (SAR) utilizing biochemical and transformed Ba/F3 cellular assays resulted in identification of potent and selective inhibitors such as compounds 9 and 45. A 2.9 Å cocrystal structure of JAK3 in complex with 9 confirms the covalent interaction. Compound 9 exhibited decent pharmacokinetic properties and is suitable for use in vivo. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology. (Chemical Equation Presented).
UR - http://www.scopus.com/inward/record.url?scp=84940515109&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.5b00710
DO - 10.1021/acs.jmedchem.5b00710
M3 - Article
C2 - 26258521
AN - SCOPUS:84940515109
SN - 0022-2623
VL - 58
SP - 6589
EP - 6606
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 16
ER -