Display options
Cite
Johnson CN, Berdini V, Beke L, et al. Fragment-based discovery of type I inhibitors of maternal embryonic leucine zipper kinase. ACS Med Chem Lett. 2014;6(1):25-30doi: 10.1021/ml5001245.
Johnson, C. N., Berdini, V., Beke, L., Bonnet, P., Brehmer, D., Coyle, J. E., Day, P. J., Frederickson, M., Freyne, E. J., Gilissen, R. A., Hamlett, C. C., Howard, S., Meerpoel, L., McMenamin, R., Patel, S., Rees, D. C., Sharff, A., Sommen, F., Wu, T., & Linders, J. T. (2015). Fragment-based discovery of type I inhibitors of maternal embryonic leucine zipper kinase. ACS medicinal chemistry letters, 6(1), 25-30. https://doi.org/10.1021/ml5001245
Johnson, Christopher N, et al. "Fragment-based discovery of type I inhibitors of maternal embryonic leucine zipper kinase." ACS medicinal chemistry letters vol. 6,1 (2015): 25-30. doi: https://doi.org/10.1021/ml5001245
Johnson CN, Berdini V, Beke L, Bonnet P, Brehmer D, Coyle JE, Day PJ, Frederickson M, Freyne EJ, Gilissen RA, Hamlett CC, Howard S, Meerpoel L, McMenamin R, Patel S, Rees DC, Sharff A, Sommen F, Wu T, Linders JT. Fragment-based discovery of type I inhibitors of maternal embryonic leucine zipper kinase. ACS Med Chem Lett. 2014 May 23;6(1):25-30. doi: 10.1021/ml5001245. eCollection 2015 Jan 08. PMID: 25589925; PMCID: PMC4291735.
Copy Download .nbib Format: NLM
Share it on

ACS Med Chem Lett. 2014 May 23;6(1):25-30. doi: 10.1021/ml5001245. eCollection 2015 Jan 08.

Fragment-based discovery of type I inhibitors of maternal embryonic leucine zipper kinase.

ACS medicinal chemistry letters

Christopher N Johnson, Valerio Berdini, Lijs Beke, Pascal Bonnet, Dirk Brehmer, Joseph E Coyle, Phillip J Day, Martyn Frederickson, Eddy J E Freyne, Ron A H J Gilissen, Christopher C F Hamlett, Steven Howard, Lieven Meerpoel, Rachel McMenamin, Sahil Patel, David C Rees, Andrew Sharff, François Sommen, Tongfei Wu, Joannes T M Linders

Affiliations

  1. Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
  2. Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340 Belgium.

PMID: 25589925 PMCID: PMC4291735 DOI: 10.1021/ml5001245

Abstract

Fragment-based drug design was successfully applied to maternal embryonic leucine zipper kinase (MELK). A low affinity (160 μM) fragment hit was identified, which bound to the hinge region with an atypical binding mode, and this was optimized using structure-based design into a low-nanomolar and cell-penetrant inhibitor, with a good selectivity profile, suitable for use as a chemical probe for elucidation of MELK biology.

Keywords: Maternal embryonic leucine zipper kinase; fragment-based drug design; structure-based optimization

References

  1. Curr Opin Oncol. 2007 Jan;19(1):55-60 - PubMed
  2. Cancer Res. 2005 Nov 1;65(21):9751-61 - PubMed
  3. PLoS One. 2013 Jul 26;8(7):e70031 - PubMed
  4. Carcinogenesis. 2010 Jun;31(6):1003-9 - PubMed
  5. Acta Crystallogr D Biol Crystallogr. 2011 May;67(Pt 5):480-7 - PubMed
  6. J Biol Chem. 2005 Dec 2;280(48):40003-11 - PubMed
  7. EMBO J. 2004 Feb 25;23(4):833-43 - PubMed
  8. J Chem Inf Model. 2012 May 25;52(5):1345-55 - PubMed
  9. Drug Discov Today. 2004 May 15;9(10):430-1 - PubMed
  10. J Med Chem. 2013 Mar 14;56(5):2016-28 - PubMed
  11. Clin Transl Sci. 2009 Feb;2(1):15-25 - PubMed
  12. Breast Cancer Res. 2009;11(4):R60 - PubMed
  13. J Biol Chem. 2013 Aug 16;288(33):24200-12 - PubMed
  14. Biochemistry. 2013 Sep 17;52(37):6380-7 - PubMed
  15. Oncotarget. 2012 Dec;3(12):1629-40 - PubMed
  16. J Neurosci Res. 2008 Jan;86(1):48-60 - PubMed
  17. J Clin Invest. 2001 Oct;108(8):1167-74 - PubMed
  18. PLoS One. 2007 Jul 04;2(7):e594 - PubMed
  19. Stem Cells. 2013 May;31(5):870-81 - PubMed
  20. Am J Physiol Endocrinol Metab. 2009 May;296(5):E969-72 - PubMed
  21. Nat Rev Drug Discov. 2012 Nov;11(11):873-86 - PubMed
  22. Breast Cancer Res. 2007;9(1):R17 - PubMed
  23. J Med Chem. 2007 May 17;50(10):2293-6 - PubMed
  24. Stem Cells. 2013 Jun;31(6):1051-63 - PubMed
  25. Cancer Res. 2010 Nov 1;70(21):8863-73 - PubMed
  26. Bioorg Med Chem Lett. 2008 Jan 1;18(1):318-23 - PubMed
  27. Bioorg Med Chem Lett. 2002 Dec 16;12(24):3537-41 - PubMed
  28. J Mol Med (Berl). 2013 Feb;91(2):237-48 - PubMed
  29. Biochem J. 2007 Dec 15;408(3):297-315 - PubMed
  30. Gene. 1997 Aug 22;195(2):295-301 - PubMed
  31. Nat Chem. 2009 Jun;1(3):187-92 - PubMed

Publication Types