title: Fragment-based discovery of type I inhibitors of maternal embryonic leucine zipper kinase.
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.
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Johnson
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Valerio
authors.initials: V
authors.lastname: Berdini
authors.affiliation: Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340 Belgium.
authors.forename: Lijs
authors.initials: L
authors.lastname: Beke
authors.affiliation: Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340 Belgium.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonnet
authors.affiliation: Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340 Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Brehmer
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Coyle
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Day
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Martyn
authors.initials: M
authors.lastname: Frederickson
authors.affiliation: Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340 Belgium.
authors.forename: Eddy J E
authors.initials: EJ
authors.lastname: Freyne
authors.affiliation: Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340 Belgium.
authors.forename: Ron A H J
authors.initials: RA
authors.lastname: Gilissen
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Christopher C F
authors.initials: CC
authors.lastname: Hamlett
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Howard
authors.affiliation: Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340 Belgium.
authors.forename: Lieven
authors.initials: L
authors.lastname: Meerpoel
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: McMenamin
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Sahil
authors.initials: S
authors.lastname: Patel
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: David C
authors.initials: DC
authors.lastname: Rees
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sharff
authors.affiliation: Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340 Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Sommen
authors.affiliation: Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340 Belgium.
authors.forename: Tongfei
authors.initials: T
authors.lastname: Wu
authors.affiliation: Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340 Belgium.
authors.forename: Joannes T M
authors.initials: JT
authors.lastname: Linders
keywords: Maternal embryonic leucine zipper kinase; fragment-based drug design; structure-based optimization