Design of potent and selective hybrid inhibitors of the mitotic kinase Nek2: structure-activity relationship, structural biology, and cellular activity

J Med Chem. 2012 Apr 12;55(7):3228-41. doi: 10.1021/jm201683b. Epub 2012 Mar 23.

Abstract

We report herein a series of Nek2 inhibitors based on an aminopyridine scaffold. These compounds have been designed by combining key elements of two previously discovered chemical series. Structure based design led to aminopyridine (R)-21, a potent and selective inhibitor able to modulate Nek2 activity in cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkenes / chemical synthesis
  • Alkenes / chemistry
  • Alkenes / pharmacology
  • Aminopyridines / chemical synthesis*
  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Benzene Derivatives / chemical synthesis
  • Benzene Derivatives / chemistry
  • Benzene Derivatives / pharmacology
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Mitosis*
  • Molecular Structure
  • NIMA-Related Kinases
  • Phosphorylation
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology

Substances

  • 4-(2-amino-5-(4-((dimethylamino)methyl)thiophen-2-yl)pyridin-3-yl)-2-((5,5,5-trifluoropent-3-en-2-yl)oxy)benzamide
  • Alkenes
  • Aminopyridines
  • Antineoplastic Agents
  • Benzamides
  • Benzene Derivatives
  • Thiophenes
  • NEK2 protein, human
  • NIMA-Related Kinases
  • Protein Serine-Threonine Kinases