title: Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase.
abstract: A novel Type II kinase inhibitor chemotype has been identified for maternal embryonic leucine zipper kinase (MELK) using structure-based ligand design. The strategy involved structural characterization of an induced DFG-out pocket by protein-ligand X-ray crystallography and incorporation of a slender linkage capable of bypassing a large gate-keeper residue, thus enabling design of molecules accessing both hinge and induced pocket regions. Optimization of an initial hit led to the identification of a low-nanomolar, cell-penetrant Type II inhibitor suitable for use as a chemical probe for MELK.
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: Janssen Research and Development, A Division of Janssen-Cilag , BP615-Chaussée du Vexin, 27106 Val-de-Reuil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Adelinet
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: Frederick
authors.initials: F
authors.lastname: Calo
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: Janssen Research and Development, A Division of Janssen-Cilag , BP615-Chaussée du Vexin, 27106 Val-de-Reuil, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Mevellec
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: Janssen Research and Development, A Division of Janssen-Cilag , BP615-Chaussée du Vexin, 27106 Val-de-Reuil, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Pasquier
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: 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