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Therapeutic Sall4 Peptide

Technology #16047

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Researchers
Prof. Daniel Geoffrey TENEN.
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Mr Tristan Rouille
Manager (65)65166906
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Tech Offer 16047 Sall4 Peptide [PDF]

Therapeutic Sall4 peptide

Technology Overview

SALL 4 is an embryonic transcription factor not expressed in normal  adult cells but has aberrant expression in leukemia and solid tumor cancers, especially in hepatocellular carcinoma (HCC).

SALL4 helps to mediate the repression of PTEN, a tumor suppressor gene, through its interaction with the nucleosome remodeling and deacetylase (NuRD) complex.  RBBp4 is one component of NuRD.

The discovery of SALL4-NuRD interaction in HCC opens a new therapeutic direction targeting the epigenetic regulator.

NUS Technology

Scientists have identified a high-affinity 10-mer peptide inhibitor (FFW) of the SALL4-RBBp4 interaction. The introduction of a FFW inhibitor abolishes the binding of SALL4 to RBBp4 and NURD, and PTEN is release from the repression.

Kinetic and stability of PEN-FFW peptide

IMAGE 1

  • At 30 min incubation, more than 90% of the peptide remained in the plasma. Extending the experiment duration by 24 hour revealed more than 50% of the peptide remained intact in the plasma after 4 h. ( Figure above)
  • High binding affinity of FFW lead with an IC50 of 23 nM.
  • Pharmacokinetic study revealed prolonged stability of the peptide and supports PEN-FFW peptide as a highly viable intravenous drug candidate.
  • Therapeutic peptide FFW inhibits SALL4+ tumor cell growth in culture and in xenograft mouse models.

IMAGE 2

  • When conjugated with Penetratin cell penetrating peptide (PEN-FFW) it showed anti-tumour efficacy in mice with hepatocellular carcinoma.

Synergistic effect with Sorafenib in Sorafenib-resistant HCC tumor

PEN-FFW peptide has significant anti-proliferative effect, inhibiting tumor growth by 85% in drug sensitive xenograft mouse model.

PEN-FFW showed synergistic effect with Sorafenib in chemo-resistant xenograft model.

Main Advantages

  • Strong understanding of the complex binding leading to a promising lead specifically targeting SALL4-NuRD complex.
  • High binding affinity of the lead with an IC50 of 23 nM.
  • Strong anti-proliferative index and thwarts tumor growth in xenograft mouse model.
  • Synergistic effect with Sorafenib and potential use in Sorafenib-resistant HCC patients.
  • Favorable pharmacokinetic profile and prolonged stability (T1/2 in human plasma ~ 4h / 90% remaining after 30 min).
  • High affinity therapeutic peptide with significant robust antitumor properties as a potential first in class drug targeting the SALL4-NuRD interaction in HCC.

Contact: Tristan Rouillé

Phone: +65-8120 6163

E-mail: trouille@nus.edu.sg

ILO Ref No: 16047

Main Inventor: Prof. Daniel Geoffrey TENEN.