ArticleACS medicinal chemistry letters2015
Pyrimidinone nicotinamide mimetics as selective tankyrase and wnt pathway inhibitors suitable for in vivo pharmacology.
Article in ACS medicinal chemistry letters, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 65 citations in OpenAlex.
- Ubiquitin pathway blockade reveals endogenous ADP-ribosylation marking PARP7 and AHR for degradation.The EMBO journal · 2026Article
- In Silico and In Vitro Analyses of Strawberry-Derived Extracts in Relation to Key Compounds' Metabolic and Anti-Tumor Effects.International journal of molecular sciences · 2025Article
- An Evolutionary Perspective on the Origin, Conservation and Binding Partner Acquisition of Tankyrases.Biomolecules · 2022Article
- Characterization of GECPAR, a noncoding RNA that regulates the transcriptional program of diffuse large B-cell lymphoma.Haematologica · 2022Article
- The Tankyrase Inhibitor OM-153 Demonstrates Antitumor Efficacy and a Therapeutic Window in Mouse Models.Cancer research communications · 2022Article
- Pyrrolotriazinone as an Underexplored Scaffold in Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Identification of response signatures for tankyrase inhibitor treatment in tumor cell lines.iScience · 2021Article
- Bioinformatic Analysis of the Nicotinamide Binding Site in Poly(ADP-Ribose) Polymerase Family Proteins.Cancers · 2021Article
- Engineering mono- and multi-valent inhibitors on a modular scaffold.Chemical science · 2021Article
- Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity.Microbiology and molecular biology reviews : MMBR · 2019Review
- Rational Design of Cell-Active Inhibitors of PARP10.ACS medicinal chemistry letters · 2019Article
- 2-Phenylquinazolinones as dual-activity tankyrase-kinase inhibitors.Scientific reports · 2018Article
- WNT Signaling in Cardiac and Vascular Disease.Pharmacological reviews · 2018Review
- Regulation of Wnt/β-catenin signalling by tankyrase-dependent poly(ADP-ribosyl)ation and scaffolding.British journal of pharmacology · 2017Review
- Niclosamide-conjugated polypeptide nanoparticles inhibit Wnt signaling and colon cancer growth.Nanoscale · 2017Article
- AZ1366: An Inhibitor of Tankyrase and the Canonical Wnt Pathway that Limits the Persistence of Non-Small Cell Lung Cancer Cells Following EGFR Inhibition.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Article
- Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.Journal of medicinal chemistry · 2017Article
- Macrocyclized Extended Peptides: Inhibiting the Substrate-Recognition Domain of Tankyrase.Journal of the American Chemical Society · 2017Article
- The novel tankyrase inhibitor (AZ1366) enhances irinotecan activity in tumors that exhibit elevated tankyrase and irinotecan resistance.Oncotarget · 2016Article
- Potent and Selective CK2 Kinase Inhibitors with Effects on Wnt Pathway Signaling in Vivo.ACS medicinal chemistry letters · 2016Article
Corrections and comments
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Authors and funding
30 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The canonical Wnt pathway plays an important role in embryonic development, adult tissue homeostasis, and cancer. Germline mutations of several Wnt pathway components, such as Axin, APC, and ß-catenin, can lead to oncogenesis. Inhibition of the poly(ADP-ribose) polymerase (PARP) catalytic domain of the tankyrases (TNKS1 and TNKS2) is known to inhibit the Wnt pathway via increased stabilization of Axin. In order to explore the consequences of tankyrase and Wnt pathway inhibition in preclinical models of cancer and its impact on normal tissue, we sought a small molecule inhibitor of TNKS1/2 with suitable physicochemical properties and pharmacokinetics for hypothesis testing in vivo. Starting from a 2-phenyl quinazolinone hit (compound 1), we discovered the pyrrolopyrimidinone compound 25 (AZ6102), which is a potent TNKS1/2 inhibitor that has 100-fold selectivity against other PARP family enzymes and shows 5 nM Wnt pathway inhibition in DLD-1 cells. Moreover, compound 25 can be formulated well in a clinically relevant intravenous solution at 20 mg/mL, has demonstrated good pharmacokinetics in preclinical species, and shows low Caco2 efflux to avoid possible tumor resistance mechanisms.
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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.