Discovery of 5-chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathway.
The myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are a heterogeneous but related group of hematological malignancies characterized by clonal expansion of one or more myeloid lineages. The discovery of the Jak2 V617F gain of function mutation highlighted Jak2 as a potential therapeutic target in the MPNs. Herein, we disclose the discovery of a series of pyrazol-3-yl pyrimidin-4-amines and the identification of 9e (AZD1480) as a potent Jak2 inhibitor. 9e inhibits signaling and proliferation of Jak2 V617F cell lines in vitro, demonstrates in vivo efficacy in a TEL-Jak2 model, has excellent physical properties and preclinical pharmacokinetics, and is currently being evaluated in Phase I clinical trials.
Department of Cancer Chemistry, AstraZeneca R&D, Boston, Massachusetts, United States. stephanos.ioannidis@astrazeneca.com
Stephanos
S
Ioannidis
Michelle L
ML
Lamb
Tao
T
Wang
Lynsie
L
Almeida
Michael H
MH
Block
Audrey M
AM
Davies
Bo
B
Peng
Mei
M
Su
Hai-Jun
HJ
Zhang
Ethan
E
Hoffmann
Caroline
C
Rivard
Isabelle
I
Green
Tina
T
Howard
Hannah
H
Pollard
Jon
J
Read
Marat
M
Alimzhanov
Geraldine
G
Bebernitz
Kirsten
K
Bell
Minwei
M
Ye
Dennis
D
Huszar
Michael
M
Zinda
D000818:Animals; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004285:Dogs; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D050791:STAT Transcription Factors / Q000378:metabolism / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
C545606:AZD 1480; D011720:Pyrazoles; D011743:Pyrimidines; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D053614:Janus Kinase 2