2. Academic Validation
  3. Fragment-based discovery of type I inhibitors of maternal embryonic leucine zipper kinase

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

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.

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