TNKS1 was discovered as an enzyme controlling the length of human telomeres and this was the first implication that tankyrase inhibitors could be useful as therapeutic agents against cancer. Later, TNKS2 was discovered and multiple roles of tankyrases in various cellular signaling pathways have implied that tankyrase inhibitors could be potential drugs especially towards different forms of cancer. The rationale for using tankyrase inhibitors in cancer therapy comes from its various functions within the cell. Tankyrases PARsylate TRF1, a shelterin complex protein protecting telomeres. The modification causes dissociation of TRF1 from the telomeres allowing extension of the telomere by a telomerase enzyme. Due to high telomerase activity, tumor cells escape cellular senescence by uncontrolled telomere extension. Inhibition of tankyrase catalytic activity in tumor cells prevents uncontrolled telomere extension, triggering cellular senescence. Tankyrase 1 is also involved in mitosis as the protein is localized to spindle poles and its catalytic activity is essential for normal bipolar spindle structure. TNKS1 depletion leads to mitotic arrest without DNA damage in HeLa cells, while some other cell lines undergo mitosis with subsequent DNA damage and arrest with a senescence-like phenotype. The cellular factors behind these events are poorly understood and remain to be elucidated before the therapeutical potential of tankyrase inhibition in this setting is evaluated. Wnt signaling MCE Chemical CHA pathway is often overactivated in cancers. The identification of tankyrases as part of the b-catenin destruction complex has put tankyrases as one of the promising drug targets regulating Wnt signaling. The central component of the canonical Wnt signaling pathway, the destruction complex, regulates the proteolysis of the downstream effector, b-catenin. When the pathway is not activated, b-catenin is constantly phosphorylated by the destruction complex and subsequently ubiquitinylated and proteolysed. Tankyrases regulate the Wnt pathway by PARsylating Axin, the rate-limiting scaffold protein of the destruction complex, leading to its degradation and activation of Wnt signaling. Inhibition of tankyrases prevents Axin degradation and deactivates Wnt signaling by lowering the levels of bcatenin. The first potent tankyrase inhibitor, XAV939, was discovered though the Wnt-responsive luciferase reporter assay. This inhibitor binds to the conserved 1380087-89-7 nicotinamide site of the enzymes and although potent, it is only modestly selective towards tankyrases. Also other inhibitors of tankyrases have been discovered through the inhibition of Wnt-responsive screening.
