Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase
ACS Medicinal Chemistry Letters2014Vol. 6(1), pp. 31–36
Citations Over TimeTop 19% of 2014 papers
Christopher N. Johnson, Christophe Adelinet, Valério Berdini, Lijs Beke, Pascal Bonnet, Dirk Brehmer, Frederick Calo, Joseph E. Coyle, Phillip J. Day, Martyn Frederickson, Eddy Freyne, Ron Gilissen, C. Hamlett, Steven Howard, Lieven Meerpoel, Laurence Mévellec, Rachel McMenamin, Élisabeth Pasquier, Sahil Patel, David C. Rees, Joannes T. M. Linders
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.
Related Papers
- → Preferential Heterodimer Formation by Isolated Leucine Zippers from Fos and Jun(1989)476 cited
- → Formation of a bispecific antibody by the use of leucine zippers(1992)210 cited
- → Influence of the Valine Zipper Region on the Structure and Aggregation of the Basic Leucine Zipper (bZIP) Domain of Activating Transcription Factor 5 (ATF5)(2012)6 cited
- → The leucine zipper domain of the Max gene product is not an autonomous dimerization site(1995)5 cited