A selective TNKS2 inhibitor for tumor-restricted WNT suppression.

Hyperactive WNT signaling is a potent cancer driver but clinical translation of WNT inhibitors has been hampered by on-target toxicities. WNT signaling can be constrained through inhibition of the PARP-family enzymes tankyrase 1 (TNKS1) and TNKS2; however, existing TNKS inhibitors suppress WNT signaling in both tumor and healthy tissues. In this Article, we show that genomic loss of TNKS1 on chromosome 8p creates a collateral vulnerability that drives a tumor-restricted dependency on TNKS2 for cellular TNKS activity. Through structure-guided design, we identify a flexible loop in TNKS2 that can be exploited to enable TNKS2-selective drug targeting and we generate a first-in-class TNKS2 inhibitor to drive selective WNT inhibition in TNKS1-deficient cell and organoid models. This work demonstrates a targetable cancer-specific vulnerability in multiple cancer types, providing a new approach for WNT-targeted therapies.