Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase.
Abstract
The PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A number of these are implicated in cancer-relevant processes, including Wnt/β-catenin signalling, Hippo signalling and telomere maintenance. The ARCs recognise a conserved tankyrase-binding peptide motif (TBM). All currently available tankyrase inhibitors target the catalytic domain and inhibit tankyrase's poly(ADP-ribosyl)ation function. However, there is emerging evidence that catalysis-independent "scaffolding" mechanisms contribute to tankyrase function. Here we report a fragment-based screening programme against tankyrase ARC domains, using a combination of biophysical assays, including differential scanning fluorimetry (DSF) and nuclear magnetic resonance (NMR) spectroscopy. We identify fragment molecules that will serve as starting points for the development of tankyrase substrate binding antagonists. Such compounds will enable probing the scaffolding functions of tankyrase, and may, in the future, provide potential alternative therapeutic approaches to inhibiting tankyrase activity in cancer and other conditions.
Collections
Subject
Humans
Escherichia coli
Tankyrases
Arginine
Peptides
Ligands
Fluorometry
Magnetic Resonance Spectroscopy
Binding Sites
Catalytic Domain
Ankyrin Repeat
Protein Binding
Kinetics
Mutation
Computer Simulation
Wnt Signaling Pathway
Research team
In Silico Medicinal Chemistry
Medicinal Chemistry 2
Structural Biology of Cell Signalling
Language
eng
Date accepted
2019-11-22
License start date
2019-12-13
Citation
Scientific reports, 2019, 9 (1), pp. 19130 - ?
Publisher
NATURE PUBLISHING GROUP