Abstract
Aberrant activation of the WNT/β-catenin signaling pathway is implicated in various types of cancers. Inhibitors targeting the Wnt signaling pathway are intensively studied in the current cancer research field, the outcomes of which remain to be determined. In this study, we have attempted to discover novel potent WNT/β-catenin pathway inhibitors through tankyrase 1/2 structure-based virtual screening. After screening more than 13.4 million compounds through molecular docking, we experimentally verified one compound, LZZ-02, as the most potent inhibitor out of 11 structurally representative top hits. LiCl-induced HEK293 cells containing TOPFlash reporter showed that LZZ-02 inhibited the transcriptional activity of β-catenin with an IC50 of 10 ± 1.2 μM. Mechanistically, LZZ-02 degrades the expression of β-catenin by stabilizing axin 2, thereby diminishing downstream proteins levels, including c-Myc and cyclin D1. LZZ-02 also inhibits the growth of colonic carcinoma cell harboring constitutively active β-catenin. More importantly, LZZ-02 effectively shrinks tumor xenograft derived from colonic cell lines. Our study successfully identified a novel tankyrase 1/2 inhibitor and shed light on a novel strategy for developing inhibitors targeting the WNT/β-catenin signaling axis.
Highlights
The highly conserved WNT/β-catenin signaling pathway plays pivotal roles in the context of development, differentiation and cellular self-renewal [1,2,3]
The human tankyrase protein family consists of tankyrase 1 (TNKS-1) and tankyrase 2 (TNKS-2), featuring a catalytic ARTD
XAV939 revealed that the tankyrase inhibitor interacts with the NAD+ binding groove of the catalytic domain [49]
Summary
The highly conserved WNT/β-catenin signaling pathway plays pivotal roles in the context of development, differentiation and cellular self-renewal [1,2,3]. Aberrant activation of WNT/β-catenin signaling has been implicated in various types of cancers [4,5]. The identification of a novel inhibitor targeting the WNT/β-catenin pathway for cancer treatment is imperatively needed in the current onco-clinic. The limited numbers of identified inhibitors targeting the Wnt/β-catenin signaling pathway restrain the scope by which the proteins of the. Being important activators of the WNT/β-catenin pathway in colon cancer, tankyrase is a hot topic for drug development and promising clinical data have been reported for several tankyrase-targeting reagents as anti-cancer drugs [6,7]. Tankyrase belong to the family of proteins known as poly (ADP)-ribose polymerases
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