Z3, a novel Jak2 tyrosine kinase small-molecule inhibitor that suppresses Jak2-mediated pathologic cell growth.

Molecular Cancer Therapeutics
Jacqueline SayyahPeter P Sayeski

Abstract

Jak2 tyrosine kinase is essential for animal development and hyperkinetic Jak2 function has been linked to a host of human diseases. Control of this pathway using Jak2-specific inhibitors would therefore potentially serve as a useful research tool and/or therapeutic agent. Here, we used a high-throughput program called DOCK to predict the ability of 20,000 small molecules to interact with a structural pocket adjacent to the ATP-binding site of murine Jak2. One small molecule, 2-methyl-1-phenyl-4-pyridin-2-yl-2-(2-pyridin-2-ylethyl)butan-1-one (herein designated as Z3), bound to Jak2 with a favorable energy score. Z3 inhibited Jak2-V617F and Jak2-WT autophosphorylation in a dose-dependent manner but was not cytotoxic to cells at concentrations that inhibited kinase activity. Z3 selectively inhibited Jak2 kinase function with no effect on Tyk2 or c-Src kinase function. Z3 significantly inhibited proliferation of the Jak2-V617F-expressing, human erythroleukemia cell line, HEL 92.1.7. The Z3-mediated reduction in cell proliferation correlated with reduced Jak2 and STAT3 tyrosine phosphorylation levels as well as marked cell cycle arrest. Finally, Z3 inhibited the growth of hematopoietic progenitor cells isolated from the bone marro...Continue Reading

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Citations

Feb 17, 2009·Current Oncology Reports·Jacqueline Sayyah, Peter P Sayeski
May 27, 2009·Current Opinion in Hematology·Giovanni Barosi, Vittorio Rosti
Mar 9, 2010·Expert Opinion on Therapeutic Patents·Róbert KissGyörgy M Keserũ
May 19, 2009·Expert Review of Anticancer Therapy·Ehab Atallah, Srdan Verstovsek
Oct 25, 2011·Experimental Hematology·Anurima MajumderPeter P Sayeski
May 19, 2009·Bioorganic & Medicinal Chemistry Letters·Róbert KissGyörgy M Keseru
Jan 16, 2014·Journal of Experimental & Clinical Cancer Research : CR·Kazuhiro YamamotoMidori Hirai
Jul 20, 2014·Methods : a Companion to Methods in Enzymology·Hai-Jing ZhongChung-Hang Leung
Aug 23, 2011·Cellular Signalling·Vaibhav KapuriaNicholas J Donato
Feb 10, 2016·Molecular Endocrinology·Manya Dhar-MascarenoEduardo J Mascareno

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