A selective TNKS2 inhibitor for tumor-restricted WNT suppression.

Genomic loss of TNKS1 on chromosome 8p creates a collateral vulnerability that makes TNKS2 dependency drive tumor-restricted WNT suppression, enabling selective TNKS2 inhibition.

• Why it matters: Hyperactive WNT signaling is a cancer driver, but WNT inhibitors have been limited by on-target toxicities in healthy tissues. A tumor-specific way to suppress WNT is needed.
• What they did: Using structure-guided design, the authors identify a flexible loop in TNKS2 to achieve TNKS2-selective targeting and generate a first-in-class TNKS2 inhibitor. They test selective WNT inhibition in TNKS1-deficient cell and organoid models.
• The result: The TNKS2 inhibitor suppresses WNT selectively in TNKS1-deficient models, demonstrating a targetable cancer-specific vulnerability across multiple cancer types and supporting WNT-targeted therapy strategies.

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