ArticleThe Journal of biological chemistry
Dissecting the molecular determinants of clinical PARP1 inhibitor selectivity for tankyrase1.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 77 citations in OpenAlex.
- Antitumor activity and structure-activity relationship of poly (ADP-ribose) polymerase (PARP)-based dual inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- NS1-Induced PARP1 Phase Transitions Prolongs Host Transcriptional Pausing to Promote Influenza A Virus Replication.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Synthesis and Characterization of Radio-Halogenated Talazoparib Analogues for Imaging and Radioligand Therapy.ACS chemical biology · 2026Article
- JPI-547, a novel dual inhibitor of PARP1/2 and tankyrase is more effective than first-generation PARP inhibitors in preclinical BRCA1/2-mutated cancer models.British journal of cancer · 2026Article
- Computational discovery of emodin-based anthraquinones as PARP-1 inhibitors with relevance to ovarian and prostate cancer.Scientific reports · 2026Article
- A Pyrone Glucoside fromBiomolecules · 2026Article
- Computational Evaluation of Novel PARP-1 Inhibitors for Breast Cancer: Docking, Molecular Dynamics, MM/GBSA, DFT and ADMET Calculations.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Synthesis of Novel Acetylene-Containing Phosphonates, Their Antiviral Activity, and Their Cytotoxicity to Different Cancer Cell Lines.Molecules (Basel, Switzerland) · 2026Article
- Rebinding drives cellular retention of small-molecule drugs with abundant targets.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Imidazole-Functionalized Thieno[3,2‑ACS omega · 2026Article
- Comparative Assessment of Free Energy Computational Methods for Revealing the Interactions Driving PARP1 Selective Inhibition.Journal of chemical information and modeling · 2026Article
- Cooperative molecular interaction networks govern PARP1 inhibitor selectivity and binding affinity.PLoS computational biology · 2026Article
- In Vitro Evaluation of PARP1 Inhibitor Olaparib-Cyanine Dye Conjugate for the Treatment of Glioblastoma.ChemMedChem · 2026Article
- Interplay Between Poly(ADP-ribosyl)ation and Specific Inner Cellular Events That Suggest Combination Strategies for Overcoming PARP Inhibitor Resistance.Pharmaceutics · 2026Review
- 2'-Nitroflavone targets PARP1 and alters cytoskeleton to inhibit triple-negative breast cancer progression.Scientific reports · 2026Article
- In vitro repositioning therapy with olaparib, temozolomide and oxaliplatin in glioblastoma cell lines: U118, U87, U251, H4 and human fibroblasts.Pharmacological reports : PR · 2025Article
- Radiosensitization Effect of PARP Inhibitor Talazoparib Involves Decreasing Mitochondrial Membrane Potential and Induction of Cellular Senescence.Current issues in molecular biology · 2025Article
- Proteome-Wide Profiling of Olaparib Interactors Using a Biotinylated Photoaffinity Probe.Chembiochem : a European journal of chemical biology · 2025Article
- Examination of Triazolinedione-Derived Dihydropyrrole Hybrid Compounds: ER Stress-Related Apoptosis in Breast Cancer Cells, Molecular Docking, and ADMET Analysis.Medicinal chemistry (Shariqah (United Arab Emirates)) · 2025Article
- Development of Drug-Induced Gene Expression Ranking Analysis (DIGERA) and Its Application to Virtual Screening for Poly (ADP-Ribose) Polymerase 1 Inhibitor.International journal of molecular sciences · 2024Article
Corrections and comments
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Authors and funding
15 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Poly-ADP-ribosyltransferases play a critical role in DNA repair and cell death, and poly(ADP-ribosyl) polymerase 1 (PARP1) is a particularly important therapeutic target for the treatment of breast cancer because of its synthetic lethal relationship with breast cancer susceptibility proteins 1 and 2. Numerous PARP1 inhibitors have been developed, and their efficacy in cancer treatment is attributed to both the inhibition of enzymatic activity and their ability to trap PARP1 on to the damaged DNA, which is cytotoxic. Of the clinical PARP inhibitors, talazoparib is the most effective at trapping PARP1 on damaged DNA. Biochemically, talazoparib is also suspected to be a potent inhibitor of PARP5a/b (tankyrase1/2 [TNKS1/2]), which is an important regulator of Wnt/β-catenin pathway. Here we show using competition experiments in cell lysate that, at a clinically relevant concentration, talazoparib can potentially bind and engage TNKS1. Using surface plasmon resonance, we measured the dissociation constants of talazoparib, olaparib, niraparib, and veliparib for their interaction with PARP1 and TNKS1. The results show that talazoparib has strong affinity for PARP1 as well as uniquely strong affinity for TNKS1. Finally, we used crystallography and hydrogen deuterium exchange mass spectroscopy to dissect the molecular mechanism of differential selectivity of these PARP1 inhibitors. From these data, we conclude that subtle differences between the ligand-binding sites of PARP1 and TNKS1, differences in the electrostatic nature of the ligands, protein dynamics, and ligand conformational energetics contribute to the different pharmacology of these PARP1 inhibitors. These results will help in the design of drugs to treat Wnt/β-catenin pathway-related cancers, such as colorectal cancers.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.