Abstract
We describe herein the structure-activity relationship (SAR) and cocrystal structures of a series of Nek2 inhibitors derived from the published polo-like kinase 1 (Plk1) inhibitor (R)-1. Our studies reveal a nonlinear SAR for Nek2 and our cocrystal structures show that compounds in this series bind to a DFG-out conformation of Nek2 without extending into the enlarged back pocket commonly found in this conformation. These observations were further investigated, and structure-based design led to Nek2 inhibitors derived from (R)-1 with more than a hundred-fold selectivity against Plk1.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Benzamides / chemical synthesis*
-
Benzamides / chemistry
-
Benzamides / pharmacology
-
Benzimidazoles / chemical synthesis*
-
Benzimidazoles / chemistry
-
Benzimidazoles / pharmacology
-
Binding Sites
-
Crystallography, X-Ray
-
Female
-
Humans
-
In Vitro Techniques
-
Male
-
Mice
-
Microsomes, Liver / drug effects
-
Microsomes, Liver / enzymology
-
Models, Molecular*
-
NIMA-Related Kinases
-
Phosphorylation
-
Protein Binding
-
Protein Conformation
-
Protein Serine-Threonine Kinases / antagonists & inhibitors*
-
Protein Serine-Threonine Kinases / chemistry
-
Stereoisomerism
-
Structure-Activity Relationship
Substances
-
4-(5-(1-methylpiperidin-4-yloxy)-1H-benzo(d)imidazol-1-yl)-2-(1-(2-(trifluoromethyl)phenyl)ethoxy)benzamide
-
Benzamides
-
Benzimidazoles
-
NEK2 protein, human
-
NIMA-Related Kinases
-
Protein Serine-Threonine Kinases
Associated data
-
PDB/2XNM
-
PDB/2XNN
-
PDB/2XNO
-
PDB/2XNP