Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Concept Videos

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

Hybridization LC-MS/MS: An alternative platform to enable specific and sensitive quantification of Antibody-ASO conjugates.

Analytica chimica acta·2026
Same author

Leveraging Kinase Drugs for Neurosciences: Discovery of Selective, CNS-Penetrant Reversible Bruton's Tyrosine Kinase Inhibitors as Therapeutics for Neuroinflammation.

Journal of medicinal chemistry·2026
Same author

Identification of aryl hydrocarbon receptor as a functional target that enhances astrocytic ApoE secretion.

Cell chemical biology·2026
Same author

GPR17 structure and agonism with small molecules and oxysterols.

bioRxiv : the preprint server for biology·2025
Same author

Acoustic ejection mass spectrometry: An integrated pipeline for ultra-high throughput screening, reactivity profiling, and potency analysis of covalent BTK inhibitors.

SLAS technology·2025
Same author

Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis.

Journal of medicinal chemistry·2024

Related Experiment Video

Updated: Aug 9, 2025

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
11:27

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

Published on: November 2, 2018

9.2K

Elucidation of the GSK3α Structure Informs the Design of Novel, Paralog-Selective Inhibitors.

Brenda Amaral1, Andrew Capacci2, Trip Anderson1

  • 1Departments of Research, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.

ACS Chemical Neuroscience
|February 22, 2023
PubMed
Summary

Researchers developed novel, selective inhibitors for Glycogen synthase kinase 3 alpha (GSK3α). This breakthrough, aided by the first GSK3α crystal structure, offers a safer therapeutic approach by avoiding Wnt/β-catenin pathway activation.

Keywords:
Alzheimer’sGSK3αGSK3βkinase inhibitortauβ-catenin

More Related Videos

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

11.4K
Identification of Novel CK2 Kinase Substrates Using a Versatile Biochemical Approach
11:11

Identification of Novel CK2 Kinase Substrates Using a Versatile Biochemical Approach

Published on: February 21, 2019

7.5K

Related Experiment Videos

Last Updated: Aug 9, 2025

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
11:27

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

Published on: November 2, 2018

9.2K
Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

11.4K
Identification of Novel CK2 Kinase Substrates Using a Versatile Biochemical Approach
11:11

Identification of Novel CK2 Kinase Substrates Using a Versatile Biochemical Approach

Published on: February 21, 2019

7.5K

Area of Science:

  • Biochemistry and structural biology
  • Medicinal chemistry
  • Neuroscience

Background:

  • Glycogen synthase kinase 3 (GSK3) is a therapeutic target, but broad inhibition causes safety issues via Wnt/β-catenin pathway activation.
  • Developing paralog-selective GSK3 inhibitors is crucial for improved safety, yet GSK3α structural data has been lacking.

Purpose of the Study:

  • To determine the crystal structure of GSK3α.
  • To design and synthesize novel GSK3α-selective inhibitors.
  • To evaluate the in vivo efficacy and selectivity of these inhibitors.

Main Methods:

  • X-ray crystallography to determine GSK3α structure.
  • Structure-based drug design and synthesis of novel inhibitors.
  • In vitro biochemical assays for selectivity and potency.
  • Chemoproteomics to assess in vivo target engagement and pathway effects.

Main Results:

  • First crystal structure of GSK3α (apo and inhibitor-bound) reported.
  • Novel compounds with up to 37-fold GSK3α selectivity over GSK3β developed.
  • In vivo studies confirmed GSK3α inhibition reduces tau phosphorylation at disease-relevant sites with high selectivity.

Conclusions:

  • The GSK3α structure provides a basis for developing highly selective inhibitors.
  • Novel GSK3α inhibitors exhibit improved potency, selectivity, and drug-like properties.
  • Targeted GSK3α inhibition offers a promising therapeutic strategy with a potentially improved safety profile.