Tankyrases as drug targets

Abstract

Tankyrase 1 and tankyrase 2 are poly(ADP-ribosyl)ases that are distinguishable from other members of the enzyme family by the structural features of the catalytic domain, and the presence of a sterile a-motif multimerization domain and an ankyrin repeat protein-interaction domain. Tankyrases are implicated in a multitude of cellular functions, including telomere homeostasis, mitotic spindle formation, vesicle transport linked to glucose metabolism, Wnt-b-catenin signaling, and viral replication. In these processes, tankyrases interact with target proteins, catalyze poly (ADP-ribosyl)ation, and regulate protein interactions and stability. The proposed roles of tankyrases in disease-relevant cellular processes have made them attractive drug targets. Recently, several inhibitors have been identified. The selectivity and potency of these small molecules can be rationalized by how they fit within the NAD + -binding groove of the catalytic domain. Some molecules bind to the nicotinamide subsite, such as generic diphtheria toxin-like ADP-ribosyltransferase inhibitors, whereas others bind to a distinct adenosine subsite that diverges from other diphtheria toxin-like ADP-ribosyltransferases and confers specificity. A highly potent dual-site inhibitor is also available. Within the last few years, tankyrase inhibitors have proved to be useful chemical probes and potential lead compounds, especially for specific cancers.

Tankyrase Inhibition Blocks Wnt/β-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer

“…This is the first Wnt/b-catenin pathway inhibitor tested in clinical trials (NCT01351103), which blocks porcupine activity and the maturation of Wnt ligands upstream in the oncogenic signaling. As tankyrases parsylate and commit other proteins to degradation in addition to AXIN1 and 2 (40,41), it could be of interest to evaluate to what extent the antitumoral capacity of tankyrase inhibitors rely on affecting any other cell processes beyond Wnt/b-catenin signaling.…”

Structure, Dynamics, and Functionality of Tankyrase Inhibitor-Induced Degradasomes

“…TNKS1/2 are involved in a wide range of cellular functions (10) and were recently shown to positively regulate the WNT/b-catenin pathway through poly-ADP-ribosylation of AXIN (11), the rate-limiting factor for destruction complex stability and function (12). Implication of TNKS1/2 as druggable targets in the WNT/b-catenin signaling pathway has generated profound research on developing novel small-molecule inhibitors (9,13,14). Inhibition of the catalytic activity of TNKS1/2 reduces WNT/b-catenin signaling in both APC wild-type cells (e.g., in HEK293) and colorectal cancer cells harboring APC truncations (e.g., in SW480; refs.…”

Insights into PARP Inhibitors’ Selectivity Using Fluorescence Polarization and Surface Plasmon Resonance Binding Assays

“…3 Tankyrases (TNKS-1 and -2) are also emerging as drug targets in oncology, but for most of the other PARPs, the precise biological functions remain largely unclear. 3,4 As the clinical trials with PARP inhibitors are in progress, the interest in understanding the extent of their cross-reactivity with other members of the ARTD family increases, especially in view of long-term therapies. 5,6 PARP inhibitors are generally designed to compete with NAD + at the enzyme active site; therefore, they have the potential to inhibit different members of the ARTD family or other enzymes that use NAD + as substrate.…”