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Updated: Jun 24, 2025

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Discovery of a potent and selective JAK1-targeting PROTAC degrader with anti-tumor activities

Xiaoyu Zhang1, Wei Wang2, Guoqiang Dong2

  • 1Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China.

Bioorganic & Medicinal Chemistry Letters
|June 5, 2024
PubMed

Insights

Researchers developed novel PROTACs targeting the JAK-STAT pathway for cancer therapy. Compound 10c effectively degraded JAK1, showing potential as an antitumor drug lead.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Aberrant Janus kinase-Signal transducer and activator of transcription (JAK-STAT) pathway signaling is implicated in various cancers.
  • Proteolysis targeting chimeras (PROTACs) offer a promising therapeutic strategy for targeting disease-associated proteins.

Purpose of the Study:

  • To design and synthesize novel CRBN-based PROTACs targeting JAK kinases using momelotinib as the warhead.
  • To evaluate the enzymatic potency, cellular antiproliferative effects, and JAK1 degradation capability of the synthesized PROTACs.

Main Methods:

  • Synthesis of a series of CRBN-directed JAK-targeting PROTACs.
  • Enzymatic and cellular assays to assess potency and antiproliferative effects.
  • Western blot analysis to confirm proteasome-dependent JAK1 degradation.

Main Results:

  • Compound 10c demonstrated significant enzymatic potency and cellular antiproliferative activity.
  • Compound 10c effectively and selectively degraded JAK1 in a proteasome-dependent manner with a DC50 of 214 nM.
  • PROTAC 10c suppressed JAK1 and its downstream signaling pathways.

Conclusions:

  • Compound 10c represents a potent and selective JAK1-degrading PROTAC.
  • Compound 10c shows potential as a novel lead compound for developing antitumor therapeutics targeting the JAK-STAT pathway.
Keywords:
Antitumor drug discoveryJAK-STAT pathwayJAK1MomelotinibPROTAC

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