Structure of human tankyrase 1 in complex with small-molecule inhibitors PJ34 and XAV939

Kirby, C.A.; Cheung, Atwood K.; Fazal, Aleem; Shultz, Michael D.; Stams, Travis

doi:10.1107/s1744309111051219

Cited by 49 publications

(55 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Their activity is not shared by non-phenanthrenes acting as potent PARP1 inhibitors [32, 33]. PJ34 (but not the non-phenanthrene potent PARP1 inhibitor ABT888) prevented the post-translational modification of tankyrase1 (apparently by polyADP-ribosylation, Figure 5A and 5C), without impairing the binding of tankyrase1 to its substrate NuMA (Figure 5B and 5C).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Exclusive destruction of mitotic spindles in human cancer cells

et al. 2017

View full text Add to dashboard Cite

We identified target proteins modified by phenanthrenes that cause exclusive eradication of human cancer cells. The cytotoxic activity of the phenanthrenes in a variety of human cancer cells is attributed by these findings to post translational modifications of NuMA and kinesins HSET/kifC1 and kif18A. Their activity prevented the binding of NuMA to α-tubulin and kinesins in human cancer cells, and caused aberrant spindles. The most efficient cytotoxic activity of the phenanthridine PJ34, caused significantly smaller aberrant spindles with disrupted spindle poles and scattered extra-centrosomes and chromosomes. Concomitantly, PJ34 induced tumor growth arrest of human malignant tumors developed in athymic nude mice, indicating the relevance of its activity for cancer therapy.

show abstract

Section: Resultsmentioning

confidence: 99%

“…PJ34, inhibiting tankyrase1 polyADP-ribosylation ([32, 33]; Figure 5), interfered with the binding of tankyrase1 and NuMA to HSET/kifC1 in cancer cells (Figures 4A and 5B). On the other hand, tankyrase1, either polyADP-ribosylated or not, was bound to γ-tubulin, which is ubiquitous in the pericentriolar material [37, 38].…”

Section: Resultsmentioning

confidence: 99%

Exclusive destruction of mitotic spindles in human cancer cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…This flexible moiety has been observed in yet a different conformation in PARP3, 42 and binding of PJ34 to two distinct sites has been observed in tankyrase-2. 43 We have solved a complex of PARP15−PJ34 earlier 44 and a structure of Pseudomonas aeruginosa ExoA−PJ34 has also been published. 45 Comparison of the crystal structure of the PARP1–PJ34 complex with those structures shows that the terminal dimethyl glycinamide moiety confers flexible van der Waals interaction propensity, enabling the compound to interact with nonpolar surfaces on either side of the NAD + binding crevice.…”

Section: Resultsmentioning

confidence: 99%

Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors

et al. 2016

View full text Add to dashboard Cite

Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.

show abstract

“…These molecules participate in stacking interactions with the side chain of histidine (aa 1201 in Tankyrase 1, aa 1048 in Tankyrase 2) and in hydrogen bonding with the backbone amides of Tyr1213 (Tyr1060 in Tankyrase 2) and Asp1198 (Asp1045 in Tankyrase 2) in the adenine dinucleotide pocket (PDB structures in Protein Data Bank, www.rcsb.org: 1UDD, 1UA9 and 4DVI) [167][168][169]. An interesting binding mechanism is exerted by the compound PJ34 (PDB code, www.rcsb.org: 3UH2) in that two molecules of PJ34 ( Table 1) can simultaneously bind to the Tankyrase PARP domain; one in the nicotineamide pocket, the other in the ADP pocket [170]. A profound review on ADP-(ribosyl)ation as old and new targets for cancer therapy is given in [171].…”

Section: Tankyrasesmentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

View full text Add to dashboard Cite

Wnt/ -catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/ -catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, -catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where -catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where -catenin levels are regulated and the nucleus where -catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of -catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellularcatenin levels. However, -catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/ -catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of -catenin at its various locations provides alternative points for therapeutic interventions.

show abstract

Structure of human tankyrase 1 in complex with small-molecule inhibitors PJ34 and XAV939

Cited by 49 publications

References 14 publications

Exclusive destruction of mitotic spindles in human cancer cells

Exclusive destruction of mitotic spindles in human cancer cells

Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Contact Info

Product

Resources

About