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ACS Med Chem Lett. 2014 May 23;6(1):25-30. doi: 10.1021/ml5001245. eCollection 2015 Jan 8.

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

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


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.


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

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