Fragment-based discovery of JAK-2 inhibitors.
Fragment-based hit identification coupled with crystallographically enabled structure-based drug design was used to design potent inhibitors of JAK-2. After two iterations from fragment 1, we were able to increase potency by greater than 500-fold to provide sulfonamide 13, a 78-nM JAK-2 inhibitor.
Antonysamy
Stephen
S
Medicinal Chemistry, SGX Pharmaceuticals, Inc, San Diego, CA 92121, USA.
Hirst
Gavin
G
Park
Frances
F
Sprengeler
Paul
P
Stappenbeck
Frank
F
Steensma
Ruo
R
Wilson
Mark
M
Wong
Melissa
M
D018360:Crystallography, X-Ray; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D013449:Sulfonamides; D053614:Janus Kinase 2