Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors

Abstract

Inhibitors of poly-ADP-ribose polymerase (PARP) family proteins are currently in clinical trials as cancer therapeutics, yet the specificity of many of these compounds is unknown. Here we evaluated a series of 185 small-molecule inhibitors, including research reagents and compounds being tested clinically, for the ability to bind to the catalytic domains of 13 of the 17 human PARP family members including the tankyrases, TNKS1 and TNKS2. Many of the best-known inhibitors, including TIQ-A, 6(5H)-phenanthridinone, olaparib, ABT-888 and rucaparib, bound to several PARP family members, suggesting that these molecules lack specificity and have promiscuous inhibitory activity. We also determined X-ray crystal structures for five TNKS2 ligand complexes and four PARP14 ligand complexes. In addition to showing that the majority of PARP inhibitors bind multiple targets, these results provide insight into the design of new inhibitors.

Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage

“…The less studied members of the superfamily, mARTDs, have recently attracted attention as potential new drug targets (Andersson et al, 2012;Ekblad et al, 2015;Morgan et al, 2015;Wahlberg et al, 2012). It is clear that the existing ARTD inhibitors are not selective and, although they inhibit certain mARTDs, they can not be used to evaluate the cellular effects of inhibiting these enzymes (Wahlberg et al, 2012).…”

“…The less studied members of the superfamily, mARTDs, have recently attracted attention as potential new drug targets (Andersson et al, 2012;Ekblad et al, 2015;Morgan et al, 2015;Wahlberg et al, 2012). It is clear that the existing ARTD inhibitors are not selective and, although they inhibit certain mARTDs, they can not be used to evaluate the cellular effects of inhibiting these enzymes (Wahlberg et al, 2012). Intracellular MARylation plays multiple roles in cancer biology as it is involved in cellular signaling events including stress and immune responses (Bütepage et al, 2015;Nicolae et al, 2014;Scarpa et al, 2013;Verheugd et al, 2013).…”

“…OUL35 contains a nicotinamide mimicking motif like most of the ARTD inhibitors reported to date (Wahlberg et al, 2012) (Figure 1A). It consists of two symmetrical benzamide motifs that could compete with the binding of NAD + in the nicotinamide binding site.…”

“…Therefore it was essential to verify the selectivity of OUL35 for ARTD10. The non-selectivity of the "PARP inhibitors" is a known issue and some efforts have recently been devoted to understanding the inhibitor profile (Haikarainen et al, 2014;Wahlberg et al, 2012). We used our established assay method Venkannagari et al, 2013) to profile the selectivity of OUL35 against the ARTDs available in our laboratory (Table 1).…”

“…An ARTD inhibitor, Olaparib, has been approved to treat ovarian cancer with BRCA mutations. However, Olaparib as well as several other inhibitors developed for ARTD1 are not specific, but they inhibit several ARTD enzymes (Wahlberg et al, 2012), which indicates that further studies are required to evaluate the contribution of different ARTDs to the phenotypes observed. This is relevant because recent studies have linked MARylating ARTDs (mARTDs) to cancer biology .…”