| Literature DB >> 25589926 |
Christopher N Johnson1, Christophe Adelinet2, Valerio Berdini1, Lijs Beke3, Pascal Bonnet3, Dirk Brehmer3, Frederick Calo1, Joseph E Coyle1, Phillip J Day1, Martyn Frederickson1, Eddy J E Freyne3, Ron A H J Gilissen3, Christopher C F Hamlett1, Steven Howard1, Lieven Meerpoel3, Laurence Mevellec2, Rachel McMenamin1, Elisabeth Pasquier2, Sahil Patel1, David C Rees1, Joannes T M Linders3.
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.Entities:
Keywords: Maternal embryonic leucine zipper kinase; fragment-based drug design; structure-based optimization
Year: 2014 PMID： 25589926 PMCID： PMC4291807 DOI： 10.1021/ml5001273
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345