Discovery of novel Jak2–Stat pathway inhibitors with extended residence time on target
| Autor: | Jiaquan Wu, Jon Read, Shan Huang, Geraldine Bebernitz, Michael Zinda, Syeed Hussain, Marat Alimzhanov, Kirsten Bell, Nancy DeGrace, Michelle Lamb, Guan Huiping, Caroline Rivard, Stephanos Ioannidis, Minwei Ye, Bo Peng |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Models Molecular Time Factors Clinical Biochemistry Molecular Conformation Pharmaceutical Science Mice Inbred Strains Pharmacology Biochemistry Substrate Specificity Mice Structure-Activity Relationship Dogs In vivo hemic and lymphatic diseases Drug Discovery STAT5 Transcription Factor Animals Humans Structure–activity relationship Phosphorylation Rats Wistar STAT3 Protein Kinase Inhibitors Molecular Biology STAT5 Cell Line Transformed Cell Proliferation Dose-Response Relationship Drug biology Drug discovery Kinase Chemistry Organic Chemistry food and beverages JAK-STAT signaling pathway Janus Kinase 2 Rats Cancer research biology.protein Molecular Medicine Female |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 23:3105-3110 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2013.02.111 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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