Related Experiment Video

Updated: Mar 18, 2026

Characterization at the Molecular Level using Robust Biochemical Approaches of a New Kinase Protein
11:23

Characterization at the Molecular Level using Robust Biochemical Approaches of a New Kinase Protein

Published on: June 30, 2019

6.8K

Functional Characterization of a Small-Molecule Inhibitor of the DKK1-LRP6 Interaction

Sara Iozzi1, Rosaria Remelli2, Barbara Lelli3

  • 1Pharmacology Department, Sienabiotech S.p.A, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; Dipartimento di Biotecnologie, Università Degli Studi di Siena, Via Fiorentina 1, 53100 Siena, Italy.

ISRN Molecular Biology
|July 12, 2016
PubMed

Insights

A novel small molecule, NCI8642, effectively blocks Dickkopf-1 (DKK1) from inhibiting Wnt signaling by targeting the LRP6 receptor. This discovery offers new therapeutic avenues for diseases linked to DKK1 dysregulation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Dickkopf-1 (DKK1) antagonizes canonical Wnt signaling by binding to LRP5/6 receptors.
  • DKK1 overexpression is implicated in diseases like osteoporosis, cancer, and neurodegeneration.
  • Targeting the DKK1-LRP5/6 interaction presents a potential therapeutic strategy.

Purpose of the Study:

  • To identify and characterize small molecules that can disrupt the DKK1-LRP6 interaction.
  • To evaluate the efficacy of such molecules in blocking DKK1's inhibitory activity on Wnt signaling.

Main Methods:

  • Surface Plasmon Resonance (SPR) technology to analyze binding kinetics.
  • In vitro binding assays to confirm displacement of DKK1 from LRP6.
  • Cellular assays to assess the functional impact on canonical Wnt signaling.

Main Results:

  • The small molecule NCI8642 was identified as a potent displacer of DKK1 from LRP6.
  • NCI8642 effectively blocked DKK1's inhibitory effects on canonical Wnt signaling in cellular assays.
  • SPR confirmed the binding interaction and displacement activity of NCI8642 with LRP6.

Conclusions:

  • The DKK1-LRP6 interaction is druggable by small molecules.
  • NCI8642 represents a promising therapeutic lead for modulating Wnt signaling.
  • This work opens new possibilities for treating DKK1-associated pathologies.

More Related Videos

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α11:27

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α

Published on: November 2, 2018

9.6K
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

9.6K

Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
6.1K
Inhibition of CDK Activity02:34

Inhibition of CDK Activity

5.6K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
13.7K
Enzyme Inhibition01:30

Enzyme Inhibition

Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
94.6K