Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase.

Autor:	Johnson CN; Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom., Adelinet C; Janssen Research and Development, A Division of Janssen-Cilag , BP615-Chaussée du Vexin, 27106 Val-de-Reuil, France., Berdini V; Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom., Beke L; Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340, Belgium., Bonnet P; Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340, Belgium., Brehmer D; Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340, Belgium., Calo F; Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom., Coyle JE; Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom., Day PJ; Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom., Frederickson M; Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom., Freyne EJ; Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340, Belgium., Gilissen RA; Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340, Belgium., Hamlett CC; Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom., Howard S; Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom., Meerpoel L; Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340, Belgium., Mevellec L; Janssen Research and Development, A Division of Janssen-Cilag , BP615-Chaussée du Vexin, 27106 Val-de-Reuil, France., McMenamin R; Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom., Pasquier E; Janssen Research and Development, A Division of Janssen-Cilag , BP615-Chaussée du Vexin, 27106 Val-de-Reuil, France., Patel S; Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom., Rees DC; Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom., Linders JT; Janssen Research and Development, A Division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, Beerse 2340, Belgium.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2014 May 23; Vol. 6 (1), pp. 31-6. Date of Electronic Publication: 2014 May 23 (Print Publication: 2015).
DOI:	10.1021/ml5001273
Abstrakt:	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.
Databáze:	MEDLINE
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