Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction

Area of Science:

• Oncology
• Biochemistry
• Drug Discovery

Background:

• Targeted kinase inhibitors are established cancer therapies, but developing phosphatase inhibitors remains challenging.
• Wild-type p53-induced phosphatase (Wip1) is an oncogenic phosphatase implicated in various cancers.
• Wip1's unique 'flap' subdomain confers structural divergence from other protein phosphatase 2C (PP2C) family members, enabling selective inhibition.

Purpose of the Study:

• To discover and characterize novel allosteric, small-molecule inhibitors targeting Wip1.
• To evaluate the therapeutic potential of Wip1 inhibition in preclinical cancer models.

Main Methods:

• Synthesis and screening of small-molecule compounds targeting Wip1.
• Biochemical assays to assess compound binding and Wip1 activity.
• In vitro studies using hematopoietic and breast tumor cell lines.
• In vivo studies involving oral administration of Wip1 inhibitors in mouse models with lymphoma xenografts.

Main Results:

• A series of allosteric Wip1 inhibitors were identified, with GSK2830371 demonstrating significant activity.
• Compound binding is dependent on Wip1's unique 'flap' subdomain, ensuring selectivity.
• GSK2830371 treatment increased Wip1 substrate phosphorylation and inhibited growth in relevant tumor cell lines.
• Oral administration of Wip1 inhibitors in mice led to pharmacodynamic effects and suppressed lymphoma xenograft growth.

Conclusions:

• GSK2830371 is the first orally active, allosteric inhibitor of Wip1 phosphatase.
• Targeting Wip1 with allosteric inhibitors represents a promising new therapeutic strategy for Wip1-amplified cancers.
• Further development of Wip1 inhibitors could offer novel treatment options for various malignancies.