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Researchers designed novel SOCS3-derived peptidomimetics to target the JAK/STAT pathway in aggressive cancers like Triple-Negative Breast Cancer (TNBC). A chimeric construct showed improved JAK2 binding and stability, offering a promising scaffold for cancer therapy.

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Area of Science:

  • Biochemistry and Molecular Biology
  • Cancer Therapeutics
  • Structural Biology

Background:

  • Suppressor of Cytokine Signaling 3 (SOCS3) normally inhibits the JAK/STAT pathway.
  • Loss of SOCS3 is linked to hyperactivated STAT3 signaling in aggressive cancers, including Triple-Negative Breast Cancer (TNBC).
  • Targeting the JAK/STAT pathway is a key strategy in cancer treatment.

Purpose of the Study:

  • To design and characterize novel SOCS3-derived peptidomimetics.
  • To investigate the potential of these mimetics in targeting dysregulated JAK/STAT signaling in cancer.
  • To explore the role of the SOCS3 BC loop in JAK2 interaction.

Main Methods:

  • Rational design of peptidomimetics based on structural analysis of the SOCS3/JAK2/Gp130 interface.
  • Synthesis of individual and chimeric peptides incorporating the BC loop.
  • Biophysical characterization using MicroScale Thermophoresis (MST), Circular Dichroism (CD), and fluorescence spectroscopy.
  • Cellular evaluation of serum stability and cytotoxicity in TNBC cell lines (MDA-MB-231, MDA-MB-468) when conjugated to a Cell-Penetrating Peptide (CPP).

Main Results:

  • A chimeric construct (KIRESS BC loop-chim) demonstrated significantly improved affinity for JAK2 (KD ∼ 10 μM) compared to isolated regions.
  • Turn-inducing motifs in the mimetics stabilized native-like conformations, enhancing serum stability.
  • Designed peptidomimetics showed good biocompatibility and promising potential for evaluating signaling-dependent effects in cancer cells.

Conclusions:

  • A structure-guided, multiregion design strategy successfully yielded improved SOCS3 proteomimetics.
  • The stabilized BC loop is a key determinant for enhanced SOCS3/JAK2 interaction.
  • These novel peptidomimetics represent a promising scaffold for targeting aberrant JAK/STAT signaling in cancer.