Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.
The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.
Department of Discovery Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, USA.
Emily J
EJ
Hanan
Anne
A
van Abbema
Kathy
K
Barrett
Wade S
WS
Blair
Jeff
J
Blaney
Christine
C
Chang
Charles
C
Eigenbrot
Sean
S
Flynn
Paul
P
Gibbons
Christopher A
CA
Hurley
Jane R
JR
Kenny
Janusz
J
Kulagowski
Leslie
L
Lee
Steven R
SR
Magnuson
Claire
C
Morris
Jeremy
J
Murray
Richard M
RM
Pastor
Tom
T
Rawson
Michael
M
Siu
Mark
M
Ultsch
Aihe
A
Zhou
Deepak
D
Sampath
Joseph P
JP
Lyssikatos
D000818:Animals; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D053614:Janus Kinase 2