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

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

doi:10.1021/ml5001245

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 8.

Authors

Christopher N Johnson¹, Valerio Berdini¹, Lijs Beke², Pascal Bonnet², Dirk Brehmer², Joseph E Coyle¹, Phillip J Day¹, Martyn Frederickson¹, Eddy J E Freyne², Ron A H J Gilissen², Christopher C F Hamlett¹, Steven Howard¹, Lieven Meerpoel², Rachel McMenamin¹, Sahil Patel¹, David C Rees¹, Andrew Sharff¹, François Sommen², Tongfei Wu², Joannes T M Linders²

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.

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.