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Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes
07:22

Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes

Published on: January 12, 2024

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Design and synthesis of JNK1-targeted PROTACs and research on the activity

Yue Guo1, Fengling Liu2, Man Chi2

  • 1Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.

Bioorganic Chemistry
|December 19, 2024
PubMed

Insights

Researchers developed novel proteolysis targeting chimeras (PROTACs) to degrade c-Jun N-Terminal Kinase (JNK1). The lead molecule PA2 demonstrated anti-JNK1 activity, offering a potential new treatment strategy for pulmonary fibrosis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Kinase dysregulation is implicated in various diseases, including cancer and fibrotic disorders.
  • c-Jun N-Terminal Kinase (JNK) is a key target for treating pulmonary fibrosis.
  • Targeted protein degradation using PROTACs offers advantages over traditional kinase inhibitors.

Purpose of the Study:

  • To develop novel JNK1-targeted PROTACs for inducing proteasomal degradation.
  • To evaluate the efficacy of developed PROTACs against JNK1.
  • To explore the therapeutic potential of JNK1-targeted PROTACs for pulmonary fibrosis.

Main Methods:

  • Synthesis of 20 JNK1-targeted PROTAC molecules.
  • Enzyme assays to assess JNK1 inhibition.
  • Protein degradation assays to confirm proteasomal degradation of JNK1.

Main Results:

  • Developed 20 JNK1-targeted PROTACs.
  • Identified PA2 as the most potent molecule.
  • PA2 demonstrated significant anti-JNK1 activity and induced JNK1 degradation.

Conclusions:

  • JNK1-targeted PROTACs are effective in degrading JNK1.
  • PA2 shows promise as a therapeutic agent for pulmonary fibrosis.
  • PROTAC technology offers a viable strategy for targeting kinases in fibrotic diseases.
Keywords:
Degradation potencyDrug discoveryPROTACc-Jun N-terminal kinase

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