Small-molecule binding of the axin RGS domain promotes β-catenin and Ras degradation

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Aberrant activation of Wnt/β-catenin and Ras pathways is common in colorectal cancers (CRCs).
• These pathways interact and promote tumor growth, making their simultaneous inhibition a promising therapeutic strategy.

Purpose of the Study:

• To identify and develop novel compounds that can simultaneously inhibit both Wnt/β-catenin and Ras signaling pathways.
• To evaluate the efficacy of a novel compound, KYA1797K, in preclinical models of colorectal cancer.

Main Methods:

• Identification of KY1220, a compound targeting the Wnt/β-catenin pathway, and synthesis of its derivative KYA1797K.
• Investigating the mechanism of action of KYA1797K, including its binding to axin and enhancement of the β-catenin destruction complex.
• Assessing the anti-tumor activity of KYA1797K in vitro and in vivo using various colorectal cancer models with APC and KRAS mutations.

Main Results:

• KYA1797K directly binds to the regulators of G-protein signaling domain of axin.
• This binding enhances GSK3β activity, leading to the degradation of β-catenin and Ras.
• KYA1797K demonstrated significant suppression of colorectal cancer growth in models with APC and KRAS mutations.

Conclusions:

• Simultaneous destabilization of β-catenin and Ras by targeting axin is a viable therapeutic strategy for colorectal cancer.
• KYA1797K shows potential as a novel therapeutic agent for CRC and other cancers driven by activated Wnt/β-catenin and Ras pathways.