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.
Christopher N Johnson  1 ,  Valerio Berdini  1 ,  Lijs Beke  2 ,  Pascal Bonnet  2 ,  Dirk Brehmer  2 ,  Joseph E Coyle  1 ,  Phillip J Day  1 ,  Martyn Frederickson  1 ,  Eddy J E Freyne  2 ,  Ron A H J Gilissen  2 ,  Christopher C F Hamlett  1 ,  Steven Howard  1 ,  Lieven Meerpoel  2 ,  Rachel McMenamin  1 ,  Sahil Patel  1 ,  David C Rees  1 ,  Andrew Sharff  1 ,  François Sommen  2 ,  Tongfei Wu  2 ,  Joannes T M Linders  2
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 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.
Products