Evaluation of potential Myt1 kinase inhibitors by TR-FRET based binding assay

Alexander Rohe; Christiane Göllner; Kanin Wichapong; Frank Erdmann; Ghassab M A Al-Mazaideh; Wolfgang Sippl; Matthias Schmidt

doi:10.1016/j.ejmech.2012.06.007

Evaluation of potential Myt1 kinase inhibitors by TR-FRET based binding assay

Eur J Med Chem. 2013 Mar:61:41-8. doi: 10.1016/j.ejmech.2012.06.007. Epub 2012 Jun 12.

Authors

Alexander Rohe¹, Christiane Göllner, Kanin Wichapong, Frank Erdmann, Ghassab M A Al-Mazaideh, Wolfgang Sippl, Matthias Schmidt

Affiliation

¹ Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, W.-Langenbeck-Str.4, 06120 Halle, Germany.

PMID: 22770610
DOI: 10.1016/j.ejmech.2012.06.007

Abstract

In the human cell cycle, the Myt1 kinase is a crucial regulator of the G2/M transition. Because this membrane-associated kinase is hard to obtain and assay, there is a distinct lack of data so far. Here we report the derivatization of a glycoglycerolipid which was shown previously to be active in a Myt1 activity assay. These compounds were tested in a binding assay together with a set of common kinase inhibitors against a full-length Myt1 expressed in a human cell line. Dasatinib exhibited nanomolar affinity whereas broad coverage inhibitors such as sunitinib and staurosporine derivatives did not show any effect. We also carried out docking studies for the most potent compounds allowing further insights into the inhibitor interaction of this kinase. The glycoglycerolipids showed no significant effects in the binding assay, endorsing the idea of a mechanism of action distant from the active site.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Fluorescence Resonance Energy Transfer*
Glycolipids / chemical synthesis
Glycolipids / chemistry
Glycolipids / pharmacology*
Humans
Membrane Proteins / antagonists & inhibitors*
Membrane Proteins / isolation & purification
Membrane Proteins / metabolism
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / isolation & purification
Protein Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / isolation & purification
Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship

Substances

Glycolipids
Membrane Proteins
Protein Kinase Inhibitors
glycerolglycolipids
Protein-Tyrosine Kinases
PKMYT1 protein, human
Protein Serine-Threonine Kinases