Design, synthesis and biological evaluation of novel aminopyrazole- and 7-azaindole-based Nek1 inhibitors and their effects on zebrafish kidney development

Bioorg Med Chem Lett. 2021 Dec 1:53:128418. doi: 10.1016/j.bmcl.2021.128418. Epub 2021 Oct 26.

Abstract

NIMA-related protein kinase Nek1 is crucially involved in cell cycle regulation, DNA repair and microtubule regulation and dysfunctions of Nek1 play key roles in amyotrophic lateral sclerosis (ALS), polycystic kidney disease (PKD) and several types of radiotherapy resistant cancer. Targeting of Nek1 could reveal a new class of radiosensitizing substances and provide useful tools to better understand the aforementioned diseases. In this report we explore substituted aminopyrazoles and 7-azaindoles as potent inhibitors for the Nek1 kinase domain and examine their effect on kidney organogenesis in Danio rerio.

Keywords: 7-Azaindole; Aminopyrazole; Nek1; Polycystic kidney disease; Zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Kidney / drug effects*
  • Kidney / growth & development
  • Kidney / metabolism
  • Molecular Structure
  • NIMA-Related Kinase 1 / antagonists & inhibitors*
  • NIMA-Related Kinase 1 / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship
  • Zebrafish

Substances

  • 7-azaindole dimer
  • Indoles
  • Protein Kinase Inhibitors
  • Pyrazoles
  • NIMA-Related Kinase 1