Small-Molecule Inhibitors of Tankyrases as Prospective Therapeutics for Cancer

Abstract

Tankyrases are multifunctional poly­(adenosine diphosphate-ribose) polymerases that regulate diverse biological processes including telomere maintenance and cellular signaling. These processes are often implicated in a number of human diseases, with cancer being the most prevalent example. Accordingly, tankyrase inhibitors have gained increasing attention as potential therapeutics. Since the discovery of XAV939 and IWR-1 as the first tankyrase inhibitors over two decades ago, tankyrase-targeted drug discovery has made significant progress. This review starts with an introduction of tankyrases, with emphasis placed on their cancer-related functions. Small-molecule inhibitors of tankyrases are subsequently delineated based on their distinct modes of binding to the enzymes. In addition to inhibitors that compete with oxidized nicotinamide adenine dinucleotide (NAD+) for binding to the catalytic domain of tankyrases, non-NAD+-competitive inhibitors are detailed. This is followed by a description of three clinically trialled tankyrase inhibitors. To conclude, some of challenges and prospects in developing tankyrase-targeted cancer therapies are discussed.

Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

“…Elevated expression of YAP has been identified in various human cancers, and as YAP inhibitor development is very limited, TNKS inhibition could be a valid alternative for hampering YAP oncogenic properties . Several TNKS inhibitors have been developed , such as compounds E7449 and STP1002 (structure undisclosed), which have progressed in clinical studies, even if compound E7449 behaves as a dual TNKS1–2 and PARP1–2 inhibitor. Other TNKS inhibitors such as RK287107 ( 1 ) and OM-153 ( 2 ) are being evaluated in preclinical studies.…”

The Role of Telomerase in Breast Cancer’s Response to Therapy

“…Tankyrase inhibitors were shown to cause more rapid telomere shortening, which could lead to cell death [ 70 , 71 ]. These include, e.g., IWR1, XAV939, and JPI-547, which are currently in clinical trials [ 4 , 72 ].…”

Pyridine-Based 1,2,4-Triazolo-Tethered Indole Conjugates Potentially Affecting TNKS and PI3K in Colorectal Cancer

“…12 The dual inhibition of PI3K/Akt and tankyrase 1/2 leads to programmed cell death through the stabilization of the βcatenin destruction complex via GSKβ. 13 Several natural and synthetic compounds bearing scaffolds like indoles, 14 1,2,4-triazoles, 15 pyridines, 16 and quinazolines 17 (see Figure 1) have individually exhibited the inhibition of either Wnt/β-catenin (tankyrase) or PI3K pathways. 18 When specific tankyrase 1/2 (8, G007-LK) and PI3K (2, BKM120) inhibitors have been applied in combination, the dual inhibition of both targets has been observed in CRC cell lines.…”

“…After phosphorylation, the activated Akt inactivates other apoptogenic factors, including GSKβ, thereby inhibiting programmed cell death . The dual inhibition of PI3K/Akt and tankyrase 1/2 leads to programmed cell death through the stabilization of the β-catenin destruction complex via GSKβ …”