Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors.
Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
Amy C
AC
Hart
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
Gretchen M
GM
Schroeder
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
Honghe
H
Wan
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
James
J
Grebinski
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
Jennifer
J
Inghrim
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
James
J
Kempson
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
Junqing
J
Guo
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
William J
WJ
Pitts
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
John S
JS
Tokarski
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
John S
JS
Sack
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
Javed A
JA
Khan
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
Jonathan
J
Lippy
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
Matthew V
MV
Lorenzi
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
Dan
D
You
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
Theresa
T
McDevitt
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
Ragini
R
Vuppugalla
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
Yueping
Y
Zhang
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
Louis J
LJ
Lombardo
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
George L
GL
Trainor
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.
Ashok V
AV
Purandare
Janus kinase 2 (JAK2); Kinase; myeloproliferative neoplasms; structure-based drug design (SBDD); thiazole