xav939 and Neoplasms

Tankyrases are multifunctional poly(adenosine diphosphate-ribose) polymerases that regulate diverse biological processes including telomere maintenance and cellular signaling. These processes are often implicated in a number of human diseases, with cancer being the most prevalent example. Accordingly, tankyrase inhibitors have gained increasing attention as potential therapeutics. Since the discovery of XAV939 and IWR-1 as the first tankyrase inhibitors over two decades ago, tankyrase-targeted drug discovery has made significant progress. This review starts with an introduction of tankyrases, with emphasis placed on their cancer-related functions. Small-molecule inhibitors of tankyrases are subsequently delineated based on their distinct modes of binding to the enzymes. In addition to inhibitors that compete with oxidized nicotinamide adenine dinucleotide (NAD

Topics: Catalytic Domain; Drug Discovery; Humans; Neoplasms; Tankyrases

Recent years have seen substantially heightened interest in the discovery of tankyrase inhibitors (TNKSi) as new promising anticancer agents. In this framework, the aim of this review article is focused on the description of potent TNKSi also endowed with disruptor activity toward the Wnt/β-catenin signaling pathway. Beginning with an overview of the most characterized TNKSi deriving from several drug design approaches and classifying them on the basis of the molecular interactions with the target, we discuss only those ones acting against Wnt cancer cell lines. In addition, comprehensive structure property relationships (SPR) emerging from the hit evolution processes and preclinical results are provided. We then review the most promising TNKSi hitherto reported in literature, acting in vivo models of Wnt-driven cancers. Some outlooks on current issues and future directions in this field are also discussed.

Topics: Animals; Antineoplastic Agents; Drug Discovery; Enzyme Inhibitors; Humans; Molecular Targeted Therapy; Neoplasms; Tankyrases; Wnt Signaling Pathway

Topics: Cell Line, Tumor; DNA Repair; Humans; Neoplasms; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases

The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is commonly overexpressed in cancers and is implicated in the development of chemoresistance. The use of drugs inhibiting MGMT has been hindered by their haematologic toxicity and inefficiency. As a different strategy to inhibit MGMT we investigated cellular regulators of MGMT expression in multiple cancers. Here we show a significant correlation between Wnt signalling and MGMT expression in cancers with different origin and confirm the findings by bioinformatic analysis and immunofluorescence. We demonstrate Wnt-dependent MGMT gene expression and cellular co-localization between active β-catenin and MGMT. Pharmacological or genetic inhibition of Wnt activity downregulates MGMT expression and restores chemosensitivity of DNA-alkylating drugs in mouse models. These findings have potential therapeutic implications for chemoresistant cancers, especially of brain tumours where the use of temozolomide is frequently used in treatment.

Topics: Animals; Antineoplastic Agents; Benzeneacetamides; beta Catenin; Brain Neoplasms; Camptothecin; Celecoxib; Cisplatin; Colorectal Neoplasms; Dacarbazine; DNA Modification Methylases; DNA Repair Enzymes; Doxorubicin; Drug Resistance, Neoplasm; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioma; Glucose-6-Phosphate Isomerase; Heterocyclic Compounds, 3-Ring; Humans; Immunoblotting; Immunohistochemistry; Irinotecan; Medulloblastoma; Mice; Neoplasm Transplantation; Neoplasms; Neuroblastoma; Pyrans; Pyrazines; Pyridines; Real-Time Polymerase Chain Reaction; Sulfones; Temozolomide; Triazoles; Tumor Suppressor Proteins; Vincristine; Wnt Proteins; Wnt Signaling Pathway

The fifth international conference on SUMO, Ubiquitin, UBL Proteins: Implications for Human Diseases, held in Houston, included topics covering the latest advances and new targets in the field of protein modification. This conference report highlights selected presentations on the structural characterization of ubiquitination and SUMOylation machinery; the regulation of ubiquitination enzymes, including E3 ligases; the functions and mechanism of action of SUMO-targeted ubiquitin ligases (STUbLs); the regulation of gene expression by SUMO; non-degradative functions of ubiquitin and SUMO in signal transduction; mechanisms and functions of ISG15 conjugation; the interaction of pathogens with host cell SUMOylation machinery; and stabilization of the Axin protein. Investigational drugs discussed include MLN-4924 (Millennium Pharmaceuticals Inc).

Topics: Allosteric Regulation; Bacterial Toxins; Communicable Diseases; Cyclopentanes; Cytokines; Enzyme Activation; Enzyme Inhibitors; Gene Expression Regulation; Heat-Shock Proteins; Hemolysin Proteins; Heterocyclic Compounds, 3-Ring; Humans; NEDD8 Protein; Neoplasms; Nuclear Proteins; Protein Processing, Post-Translational; Pyrimidines; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Tankyrases; Transcription Factors; Ubiquitin; Ubiquitin-Activating Enzymes; Ubiquitin-Conjugating Enzymes; Ubiquitin-Protein Ligases; Ubiquitination; Ubiquitins