Jadomycin B, an Aurora-B kinase inhibitor discovered through virtual screening

Molecular Cancer Therapeutics
Da-Hua FuShuyi Si

Abstract

Aurora kinases have emerged as promising targets for cancer therapy because of their critical role in mitosis. These kinases are well-conserved in all eukaryotes, and IPL1 gene encodes the single Aurora kinase in budding yeast. In a virtual screening attempt, 22 compounds were identified from nearly 15,000 microbial natural products as potential small-molecular inhibitors of human Aurora-B kinase. One compound, Jadomycin B, inhibits the growth of ipl1-321 temperature-sensitive mutant more dramatically than wild-type yeast cells, raising the possibility that this compound is an Aurora kinase inhibitor. Further in vitro biochemical assay using purified recombinant human Aurora-B kinase shows that Jadomycin B inhibits Aurora-B activity in a dose-dependent manner. Our results also indicate that Jadomycin B competes with ATP for the kinase domain, which is consistent with our docking prediction. Like other Aurora kinase inhibitors, Jadomycin B blocks the phosphorylation of histone H3 on Ser10 in vivo. We also present evidence suggesting that Jadomycin B induces apoptosis in tumor cells without obvious effects on cell cycle. All the results indicate that Jadomycin B is a new Aurora-B kinase inhibitor worthy of further investigation.

References

Jul 7, 1999·Journal of the National Cancer Institute·H KatayamaM Tatsuka
Oct 26, 2000·Japanese Journal of Cancer Research : Gann·T TakahashiS Saji
Jan 3, 2001·The Journal of Cell Biology·D A SkoufiasR L Margolis
Feb 13, 2001·Trends in Cell Biology·R R AdamsW C Earnshaw
Apr 6, 2001·International Journal of Cancer. Journal International Du Cancer·Y MiyoshiS Noguchi
Apr 30, 2003·The Journal of Cell Biology·Claire DitchfieldStephen S Taylor
Apr 28, 2004·Current Opinion in Genetics & Development·Patrick MeraldiErich A Nigg
Jul 14, 2004·The Journal of Cell Biology·Reto GassmannWilliam C Earnshaw
May 4, 2005·Molecular Cell·Fabio SessaAndrea Musacchio
Jul 28, 2005·Journal of Cell Science·Christopher J MorrowStephen S Taylor
Sep 15, 2005·The Journal of Antibiotics·Jian-Ting ZhengKe-Qian Yang
Jan 3, 2006·Developmental Biology·Chieh-Ju C TangTang K Tang
Apr 1, 2006·Gene Expression·Yong-Shiang LinChi-Ying F Huang
Dec 29, 2006·Molecular Endocrinology·Sarah KimminsPaolo Sassone-Corsi
Jan 9, 2007·Current Opinion in Genetics & Development·Marcos Malumbres, Mariano Barbacid
Sep 13, 2007·Nature Reviews. Molecular Cell Biology·Sandrine RuchaudWilliam C Earnshaw
Nov 6, 2007·Frontiers in Bioscience : a Journal and Virtual Library·Yanchang Wang

❮ Previous
Next ❯

Citations

Feb 22, 2012·Investigational New Drugs·Madhu KollareddyMarian Hajduch
Apr 20, 2010·Journal of Computer-aided Molecular Design·Natasja Brooijmans, Christine Humblet
Nov 6, 2010·Journal of Computer-aided Molecular Design·Natasja BrooijmansChristine Humblet
Feb 9, 2010·Acta Pharmacologica Sinica·Mm NeazSeung Joo Cho
Aug 12, 2009·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Jan-Bart M KoorstraAnirban Maitra
May 17, 2011·Journal of Translational Medicine·Yi LiJian-Dong Jiang
Jun 1, 2010·Expert Opinion on Drug Discovery·Alan L HarveyBlair F Johnston
Mar 3, 2015·Pharmacology Research & Perspectives·Steven R HallKerry B Goralski
Feb 16, 2013·Biochimica Et Biophysica Acta·Kevin R W NgoeiMarie A Bogoyevitch
Apr 15, 2016·Expert Opinion on Drug Discovery·D DubeP Kaur
Aug 27, 2015·Organic & Biomolecular Chemistry·Camilo F Martinez-FarinaDavid L Jakeman
Mar 9, 2012·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jikai LiuShuyi Si
Jul 11, 2009·Organic & Biomolecular Chemistry·Kirstin Scherlach, Christian Hertweck
Apr 28, 2010·Chembiochem : a European Journal of Chemical Biology·Yihua ChenKeqian Yang
Jan 11, 2012·Natural Product Reports·Jing LiuQingsong Liu
Oct 12, 2018·Anti-cancer Agents in Medicinal Chemistry·Rabia HameedShagufta Perveen
Sep 15, 2017·The Journal of Pharmacology and Experimental Therapeutics·Steven R HallKerry B Goralski
Aug 26, 2017·Future Medicinal Chemistry·Abdurrahman OlğaçErden Banoglu
Aug 18, 2009·The Oncologist·David S BossJan H M Schellens
Apr 1, 2012·European Journal of Organic Chemistry·Ehesan U Sharif, George A O'Doherty
Mar 3, 2012·Journal of Neuro-oncology·Roberto Jose DiazJames T Rutka
May 23, 2019·Frontiers in Genetics·Joseph D Romano, Nicholas P Tatonetti
May 15, 2013·Chemistry : a European Journal·Xiaoyu Yang, Biao Yu
Nov 18, 2020·Biomolecules·Andrea Baier, Ryszard Szyszka
Jan 15, 2009·Journal of Medicinal Chemistry·Mohane Selvaraj CoumarHsing-Pang Hsieh
May 11, 2021·3 Biotech·Muthu Kumar ThirunavukkarasuRamanathan Karuppasamy
Oct 29, 2021·Pharmacology Research & Perspectives·Esther P BonittoKerry B Goralski

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis