title: Discovery of novel Jak2-Stat pathway inhibitors with extended residence time on target.
abstract: The discovery of the activating mutation V617F in the JH2 domain of Jak2 and the modulation of oncogenic Stat3 by Jak2 inhibitors have spurred a great interest in the inhibition of the Jak2/Stat pathway in oncology. In this Letter, we communicate the discovery of novel inhibitors of the Jak2/Stat5 axis, the N-(1H-pyrazol-3-yl)pyrimidin-2-amino derivatives. The rationale, synthesis and biological evaluation of these derivatives are reported. Two lead analogs from this series, 6 and 9, displayed prolonged residence time on Jak2, at enzymatic level. Although 6 and 9 exhibited moderate selectivity in a selected kinase panel, we chose to test these inhibitors in vivo as a consequence to their long residence time. However, extended inhibition of Jak2 due to the long residence time, in the form of inhibiting phosphorylation of downstream Stat5, was not recapitulated in an in vivo setting.
authors.affiliation: Department of Cancer Chemistry, Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Huiping
authors.initials: H
authors.lastname: Guan
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Lamb
authors.forename: Bo
authors.initials: B
authors.lastname: Peng
authors.forename: Shan
authors.initials: S
authors.lastname: Huang
authors.forename: Nancy
authors.initials: N
authors.lastname: Degrace
authors.forename: Jon
authors.initials: J
authors.lastname: Read
authors.forename: Syeed
authors.initials: S
authors.lastname: Hussain
authors.forename: Jiaquan
authors.initials: J
authors.lastname: Wu
authors.forename: Caroline
authors.initials: C
authors.lastname: Rivard
authors.forename: Marat
authors.initials: M
authors.lastname: Alimzhanov
authors.forename: Geraldine
authors.initials: G
authors.lastname: Bebernitz
authors.forename: Kirsten
authors.initials: K
authors.lastname: Bell
authors.forename: Minwei
authors.initials: M
authors.lastname: Ye
authors.forename: Michael
authors.initials: M
authors.lastname: Zinda
authors.forename: Stephanos
authors.initials: S
authors.lastname: Ioannidis
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D008968:Molecular Conformation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D053614:Janus Kinase 2