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Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2.

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Qiu W, Lam R, Voytyuk O, Romanov V, Gordon R, Gebremeskel S, Vodsedalek J, Thompson C, Beletskaya I, Battaile KP, Pai EF, Rottapel R, Chirgadze NY
OpenAccess logo Acta Crystallogr D Biol Crystallogr 70 2740-53 (2014)
Related entries: 4pml, 4pnl, 4pnm, 4pnn, 4pnq, 4pnr, 4pns, 4pnt, 4tju, 4tjw, 4tjy, 4tk0, 4tk5, 4tkf, 4tki

Cited: 13 times
EuropePMC logo PMID: 25286857

Abstract

The poly(ADP-ribose) polymerase (PARP) family represents a new class of therapeutic targets with diverse potential disease indications. PARP1 and PARP2 inhibitors have been developed for breast and ovarian tumors manifesting double-stranded DNA-repair defects, whereas tankyrase 1 and 2 (TNKS1 and TNKS2, also known as PARP5a and PARP5b, respectively) inhibitors have been developed for tumors with elevated β-catenin activity. As the clinical relevance of PARP inhibitors continues to be actively explored, there is heightened interest in the design of selective inhibitors based on the detailed structural features of how small-molecule inhibitors bind to each of the PARP family members. Here, the high-resolution crystal structures of the human TNKS2 PARP domain in complex with 16 various PARP inhibitors are reported, including the compounds BSI-201, AZD-2281 and ABT-888, which are currently in Phase 2 or 3 clinical trials. These structures provide insight into the inhibitor-binding modes for the tankyrase PARP domain and valuable information to guide the rational design of future tankyrase-specific inhibitors.

Articles - 4tkg mentioned but not cited (2)

  1. Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2. Qiu W, Lam R, Voytyuk O, Romanov V, Gordon R, Gebremeskel S, Vodsedalek J, Thompson C, Beletskaya I, Battaile KP, Pai EF, Rottapel R, Chirgadze NY. Acta Crystallogr D Biol Crystallogr 70 2740-2753 (2014)
  2. Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1). Zhang Z, Chang X, Zhang C, Zeng S, Liang M, Ma Z, Wang Z, Huang W, Shen Z. J Enzyme Inhib Med Chem 35 1606-1615 (2020)


Reviews citing this publication (5)

  1. Regulation of Wnt/β-catenin signalling by tankyrase-dependent poly(ADP-ribosyl)ation and scaffolding. Mariotti L, Pollock K, Guettler S. Br J Pharmacol 174 4611-4636 (2017)
  2. Recent advancements in PARP inhibitors-based targeted cancer therapy. Zhou P, Wang J, Mishail D, Wang CY. Precis Clin Med 3 187-201 (2020)
  3. Concepts and Molecular Aspects in the Polypharmacology of PARP-1 Inhibitors. Passeri D, Camaioni E, Liscio P, Sabbatini P, Ferri M, Carotti A, Giacchè N, Pellicciari R, Gioiello A, Macchiarulo A. ChemMedChem 11 1219-1226 (2016)
  4. Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies. Padella A, Ghelli Luserna Di Rorà A, Marconi G, Ghetti M, Martinelli G, Simonetti G. J Hematol Oncol 15 10 (2022)
  5. ADP-ribose contributions to genome stability and PARP enzyme trapping on sites of DNA damage; paradigm shifts for a coming-of-age modification. Rouleau-Turcotte É, Pascal JM. J Biol Chem 299 105397 (2023)

Articles citing this publication (6)



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