Top II inhibitors(Topoisomerase II inhibitors), URAT1 inhibitors(Uric acid transporter 1 inhibitors), XO inhibitors(Xanthine dehydrogenase inhibitors)

Therapeutic Areas

NeoplasmsOther Diseases

Active Indication-

Inactive Indication

HyperuricemiaNeoplasms

Originator Organization

Chemtura Corp.

Active Organization-

Inactive Organization

Chemtura Corp.ACQUIST THERAPEUTICS, INC.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

Structure

Molecular FormulaC11H9N3O3S

InChIKeyJARCFMKMOFFIGZ-UHFFFAOYSA-N

CAS Registry97534-21-9

100 Clinical Results associated with Merbarone

100 Translational Medicine associated with Merbarone

100 Patents (Medical) associated with Merbarone

Literatures (Medical) associated with Merbarone

01 Oct 2022·Data in Brief

Data of transcriptional effects of the merbarone-mediated inhibition of TOP2

Article

Author: Divina, Federico ; Jimeno-González, Silvia ; Martínez-García, Pedro Manuel ; Delgado-Chaves, Fernando M ; Gómez-Vela, Francisco ; Cortés-Ledesma, Felipe ; Herrero-Ruiz, Andrés

Type II DNA topoisomerases relax topological stress by transiently gating DNA passage in a controlled cut-and-reseal mechanism that affects both DNA strands. Therefore, they are essential to overcome topological problems associated with DNA metabolism. Their aberrant activity results in the generation of DNA double-strand breaks, which can seriously compromise cell survival and genome integrity. Here, we profile the transcriptome of human-telomerase-immortalized retinal pigment epithelial 1 (RPE-1) cells when treated with merbarone, a drug that catalytically inhibits type II DNA topoisomerases. We performed RNA-Seq after 4 and 8 h of merbarone treatment and compared transcriptional profiles versus untreated samples. We report raw sequencing data together with lists of gene counts and differentially expressed genes.

09 Apr 2020·Journal of Medicinal ChemistryQ1 · MEDICINE

Design, Synthesis, Dynamic Docking, Biochemical Characterization, and in Vivo Pharmacokinetics Studies of Novel Topoisomerase II Poisons with Promising Antiproliferative Activity

Q1 · MEDICINE

Article

Author: Franco-Ulloa, Sebastian ; Brindani, Nicoletta ; Bertozzi, Sine Mandrup ; De Vivo, Marco ; Nigro, Michela ; Girotto, Stefania ; Summa, Maria ; Ottonello, Giuliana ; Bertorelli, Rosalia ; Armirotti, Andrea ; Kuriappan, Jissy Akkarapattiakal ; Arencibia, Jose M.

We previously reported a first set of hybrid topoisomerase II (topoII) poisons whose chemical core merges key pharmacophoric elements of etoposide and merbarone, which are two well-known topoII blockers. Here, we report on the expansion of this hybrid molecular scaffold and present 16 more hybrid derivatives that have been designed, synthesized, and characterized for their ability to block topoII and for their overall drug-like profile. Some of these compounds act as topoII poison and exhibit good solubility, metabolic (microsomal) stability, and promising cytotoxicity in three cancer cell lines (DU145, HeLa, A549). Compound 3f (ARN24139) is the most promising drug-like candidate, with a good pharmacokinetics profile in vivo. Our results indicate that this hybrid new chemical class of topoII poisons deserves further exploration and that 3f is a favorable lead candidate as a topoII poison, meriting future studies to test its efficacy in in vivo tumor models.

01 Oct 2019·Molecular OncologyQ2 · MEDICINE

Oncofetal HMGA2 attenuates genotoxic damage induced by topoisomerase II target compounds through the regulation of local DNA topology

Q2 · MEDICINE

ArticleOA

Author: Dröge, Peter ; Ahmed, Syed Moiz

Rapidly dividing cells maintain chromatin supercoiling homeostasis via two specialized classes of enzymes, DNA topoisomerase type 1 and 2 (TOP1/2). Several important anticancer drugs perturb this homeostasis by targeting TOP1/2, thereby generating genotoxic DNA damage. Our recent studies indicated that the oncofetal chromatin structuring high‐mobility group AT‐hook 2 (HMGA2) protein plays an important role as a DNA replication fork chaperone in coping with DNA topological ramifications that occur during replication stress, both genomewide and at fragile sites such as subtelomeres. Intriguingly, a recent large‐scale clinical study identified HMGA2 expression as a sole predicting marker for relapse and poor clinical outcomes in 350 acute myeloid leukemia (AML) patients receiving combinatorial treatments that targeted TOP2 and replicative DNA synthesis. Here, we demonstrate that HMGA2 significantly enhanced the DNA supercoil relaxation activity of the drug target TOP2A and that this activator function is mechanistically linked to HMGA2's known ability to constrain DNA supercoils within highly compacted ternary complexes. Furthermore, we show that HMGA2 significantly reduced genotoxic DNA damage in each tested cancer cell model during treatment with the TOP2A poison etoposide or the catalytic TOP2A inhibitor merbarone. Taken together with the recent clinical data obtained with AML patients targeted with TOP2 poisons, our study suggests a novel mechanism of cancer chemoresistance toward combination therapies administering TOP2 poisons or inhibitors. We therefore strongly argue for the future implementation of trials of HMGA2 expression profiling to stratify patients before finalizing clinical treatment regimes.

100 Deals associated with Merbarone

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperuricemia	Phase 2	US	ACQUIST THERAPEUTICS, INC.	07 Sep 2019
Neoplasms	Phase 2	-	Chemtura Corp.	-

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