NLS-StAx-h

Wnt Signaling & Transcriptional Regulation Peptide

NLS-StAx-h is a cell-permeable hydrocarbon-stapled α-helical peptide designed to inhibit protein protein interactions (PPI) involving β-catenin at the terminal stage of the Wnt signaling pathway. NLS-StAx-h is an optimized variant of the original StAx stapled peptide, incorporating homo-arginine substitutions and an N-terminal nuclear localization sequence (NLS) to enhance cellular and nuclear uptake. This peptide is widely used as a research tool to study Wnt-dependent transcription and β-catenin mediated signaling.

Disease Target

Targets Wnt-driven cancers including colorectal cancer (≈90% Wnt-mutated), melanoma, and leukemias by blocking nuclear β-catenin–mediated oncogenic transcription.

Stapling Strategy

NLS-StAx-h is synthesized using Fmoc-(S)-2-(4-pentenyl)alanine (Fmoc-(S5)-OH, CAS: 288617-73-2), and incorporated at i,i+4 positions (13,17) during solid-phase peptide synthesis (SPPS). A ruthenium-catalyzed ring-closing olefin metathesis generates the (CH₂)₄ hydrocarbon staple, stabilizing the α-helical structure and enhancing cellular uptake and target engagement.

Technical specification

	Sequency :	PKKKRKVRRWPR(S5)ILD(S5)HVRRVWR
	MW :	3216.93 g/mol
	Purity :	> 95%
	Counter-Ion :	TFA Salts
	Delivery format :	Lyophilized
	CAS number :	2872559-21-0

Price

Product	Size	Price €	Price $
SB325-1mg	1 mg	792	951
SB325-5mg	5 mg	964	1157
SB325-10mg	10 mg	1291	1550

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References

2017 Aug 17;24(8):958-968.e5. doi: 10.1016/j.chembiol.2017.06.013. Epub 2017 Jul 27.

Cell Permeable Stapled Peptide Inhibitor of Wnt Signaling that Targets β-Catenin Protein-Protein Interactions

Abstract

The Wnt signaling pathway plays a critical role in cell proliferation and differentiation, thus it is often associated with diseases such as cancers. Unfortunately, although attractive, developing anti-cancer strategy targeting Wnt signaling has been challenging given that the most attractive targets are involved in protein-protein interactions (PPIs). Here, we develop a stapled peptide inhibitor that targets the interaction between β-catenin and T cell factor/lymphoid enhancer-binding factor transcription factors, which are crucially involved in Wnt signaling. Our integrative approach combines peptide stapling to optimize proteolytic stability, with lessons learned from cell-penetrating peptide (CPP) design to maximize cellular uptake resulting in NLS-StAx-h, a selective, cell permeable, stapled peptide inhibitor of oncogenic Wnt signaling that efficiently inhibits β-catenin-transcription factor interactions. We expect that this type of integrative strategy that endows stapled peptides with CPP features will be generally useful for developing inhibitors of intracellular PPIs.

21 January 2021 https://doi.org/10.1002/med.21787

Direct targeting of β-catenin in the Wnt signaling pathway: Current progress and perspectives

Abstract

Aberrant activation of the Wnt/β-catenin signaling circuit is associated with cancer recurrence and relapse, cancer invasion and metastasis, and cancer immune evasion. Direct targeting of β-catenin, the central hub in this signaling pathway, is a promising strategy to suppress the hyperactive β-catenin signaling but has proven to be highly challenging. Substantial efforts have been made to discover compounds that bind with β-catenin, block β-catenin-mediated protein–protein interactions, and suppress β-catenin signaling. Herein, we characterize potential small-molecule binding sites in β-catenin, summarize bioactive small molecules that directly target β-catenin, and review structure-based inhibitor optimization, structure–activity relationship, and biological activities of reported inhibitors. This knowledge will benefit future inhibitor development and β-catenin-related drug discovery.

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