3ZMM

Inhibitors of Jak2 Kinase domain

Summary for 3ZMM

• Entry DOI: 10.2210/pdb3zmm/pdb
• Descriptor: TYROSINE-PROTEIN KINASE JAK2, 5-FLUORO-4-[(1S)-1-(5-FLUOROPYRIMIDIN-2-YL)ETHOXY]-N-(5-METHYL-1H-PYRAZOL-3-YL)-6-MORPHOLINO-PYRIMIDIN-2-AMINE, ACETYL GROUP, ... (4 entities in total)
• Functional Keywords: transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Endomembrane system ; Peripheral membrane protein : O60674
• Total number of polymer chains: 2
• Total formula weight: 71160.59

Authors

Read, J.,Green, I.,Pollard, H.,Howard, T.,Mott, R. (deposition date: 2013-02-11, release date: 2013-04-17, Last modification date: 2023-12-20)

Primary citation

Guan, H.,Lamb, M.L.,Peng, B.,Huang, S.,Degrace, N.,Read, J.,Hussain, S.,Wu, J.,Rivard, C.,Alimzhanov, M.,Bebernitz, G.,Bell, K.,Ye, M.,Zinda, M.,Ioannidis, S.
Discovery of Novel Jak2-Stat Pathway Inhibitors with Extended Residence Time on Target.
Bioorg.Med.Chem.Lett., 23:3105-, 2013

PubMed 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.

PubMed: 23562594
DOI: 10.1016/J.BMCL.2013.02.111

Experimental method

X-RAY DIFFRACTION (2.51 Å)