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

Discovery of MK-2118, a Small-Molecule Agonist of STING.

ACS medicinal chemistry letters·2026
Same author

Discovery of Potent and Selective Benzothiophene Difluoromethyl Phosphonate (DFMP) PTPN2/N1-Dual Inhibitors.

Journal of medicinal chemistry·2026
Same author

Correction to "Discovery of Potent, Selective, CNS-Penetrant Macrocyclic LRRK2 Inhibitors for the Treatment of Parkinson's Disease".

Journal of medicinal chemistry·2026
Same author

From KRAS<sup><i>G12D</i></sup> to Pan-KRAS Inhibitors─A Journey Enabled by Synthetic Innovation and Structure-Based Drug Design.

Journal of medicinal chemistry·2026
Same author

Discovery of Potent, Selective, CNS-Penetrant Macrocyclic LRRK2 Inhibitors for the Treatment of Parkinson's Disease.

Journal of medicinal chemistry·2026
Same author

The Discovery of Bridged Benzoazepine Amides as Selective Allosteric Modulators of RIPK1.

ACS medicinal chemistry letters·2025

Related Experiment Video

Updated: Nov 12, 2025

Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System
05:55

Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System

Published on: December 21, 2019

6.9K

Identification of Potent Reverse Indazole Inhibitors for HPK1.

Elsie C Yu1, Joey L Methot1, Xavier Fradera2

  • 1Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts, 02115, United States.

ACS Medicinal Chemistry Letters
|March 19, 2021
PubMed
Summary

Researchers optimized a kinase inhibitor targeting Hematopoietic Progenitor Kinase 1 (HPK1), a key regulator in T-cell activation. The novel compound demonstrates potent and selective inhibition, showing promise for antitumor immunotherapy applications.

More Related Videos

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
10:29

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors

Published on: May 9, 2025

1.8K
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

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

Published on: January 22, 2019

9.3K

Related Experiment Videos

Last Updated: Nov 12, 2025

Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System
05:55

Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System

Published on: December 21, 2019

6.9K
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
10:29

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors

Published on: May 9, 2025

1.8K
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

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

Published on: January 22, 2019

9.3K

Area of Science:

  • Medicinal Chemistry
  • Immunology
  • Structural Biology

Background:

  • Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor (TCR)-mediated T-cell activation.
  • HPK1 is recognized as a promising target for novel antitumor immunotherapy strategies.

Purpose of the Study:

  • To identify potent and selective inhibitors of HPK1 through systematic structural optimization.
  • To elucidate the structural basis for the interaction between inhibitors and HPK1.
  • To evaluate the in vitro and in vivo efficacy of optimized HPK1 inhibitors.

Main Methods:

  • Systematic two-dimensional diversity screening of pyrazolopyridines to optimize kinase inhibitor 4.
  • X-ray crystallography to determine the binding mode of inhibitors with HPK1.
  • Computational studies to analyze protein-ligand interactions and torsional profiles.
  • In vitro assays using human peripheral blood mononuclear cells (PBMCs) to assess SLP76 phosphorylation inhibition.
  • In vivo pharmacokinetic studies in rats to evaluate compound clearance and bioavailability.

Main Results:

  • Identification of potent and selective HPK1 inhibitors through structural optimization.
  • Crystallographic data revealed key interactions, including a water-mediated interaction with Asp155 and a salt bridge to Asp101, facilitated by optimized heterocyclic solvent fronts.
  • Computational analysis highlighted differences in torsional profiles contributing to favorable protein-ligand interactions.
  • Optimized reverse indazole inhibitor 36 effectively inhibited SLP76 phosphorylation in human PBMCs.
  • Compound 36 demonstrated low clearance and good bioavailability in rat models.

Conclusions:

  • Structural optimization of pyrazolopyridine-based inhibitors led to potent and selective HPK1 inhibitors.
  • Understanding the specific interactions with HPK1 (Asp155, Asp101) is crucial for enhancing inhibitor potency and selectivity.
  • The identified reverse indazole inhibitor 36 shows potential as a therapeutic agent for antitumor immunotherapy due to its efficacy and favorable pharmacokinetic properties.