ChemInform Abstract: Latent Inhibitors. Part 6. Inhibition of Dihydroorotate Dehydrogenase by Substituted 5‐Benzylhydantoins.

Howie, C.; Suckling, Colin J.; Wood, H. C. S.

doi:10.1002/chin.199108192

Cited by 2 publications

(2 citation statements)

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“…One other hit, 609515, also possesses reasonable physicochemical properties (logP = 2.31, topological polar surface area = 87.7) and even showed a trend toward selectively inhibiting BRCA1 mutated cells versus cells with restored BRCA1 activity ( Fig 2B ). In addition to inhibiting ssDNA binding to RAD52, compounds possessing the benzylhydantoin chemical scaffold of 609515 are known to be inhibitors of Bcl-2 [ 24 ] and dihydroorotate dehydrogenase [ 25 ], two other potential anti-cancer mechanisms. This hit might represent a starting point for a multi-mechanism antineoplastic hit to lead project.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection

et al. 2016

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It has been reported that inhibition of RAD52 either by specific shRNA or a small peptide aptamer induced synthetic lethality in tumor cell lines carrying BRCA1 and BRCA2 inactivating mutations. Molecular docking was used to screen two chemical libraries: 1) 1,217 FDA approved drugs, and 2) 139,735 drug-like compounds to identify candidates for interacting with DNA binding domain of human RAD52. Thirty six lead candidate compounds were identified that were predicted to interfere with RAD52 –DNA binding. Further biological testing confirmed that 9 of 36 candidate compounds were able to inhibit the binding of RAD52 to single-stranded DNA in vitro. Based on molecular binding combined with functional assays, we propose a model in which the active compounds bind to a critical “hotspot” in RAD52 DNA binding domain 1. In addition, one of the 9 active compounds, adenosine 5’-monophosphate (A5MP), and also its mimic 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) 5’ phosphate (ZMP) inhibited RAD52 activity in vivo and exerted synthetic lethality against BRCA1 and BRCA2–mutated carcinomas. These data suggest that active, inhibitory RAD52 binding compounds could be further refined for efficacy and safety to develop drugs inducing synthetic lethality in tumors displaying deficiencies in BRCA1/2-mediated homologous recombination.

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Section: Resultsmentioning

confidence: 99%

Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection

et al. 2016

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“…Hydantoins such as 100 (Figure ) were reported to be inhibitors of Clostridium oroticum DHODH . Along with additional work, , a recent report on a related series is probably a good reason to consider today such an inhibition with caution . Following a biochemical screening, a series of pyrazoles featuring three amide functions, such as compound 101 , were found to selectively inhibit the ubiquinone binding site of H. pylori DHODH .…”

Section: Inhibitors Of Dihydroorotate Dehydrogenase and Their Usesmentioning

confidence: 99%

On Dihydroorotate Dehydrogenases and Their Inhibitors and Uses

et al. 2013

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Proper nucleosides availability is crucial for the proliferation of living entities (eukaryotic cells, parasites, bacteria, and virus). Accordingly, the uses of inhibitors of the de novo nucleosides biosynthetic pathways have been investigated in the past. In the following we have focused on dihydroorotate dehydrogenase (DHODH), the fourth enzyme in the de novo pyrimidine nucleosides biosynthetic pathway. We first described the different types of enzyme in terms of sequence, structure, and biochemistry, including the reported bioassays. In a second part, the series of inhibitors of this enzyme along with a description of their potential or actual uses were reviewed. These inhibitors are indeed used in medicine to treat autoimmune diseases such as rheumatoid arthritis or multiple sclerosis (leflunomide and teriflunomide) and have been investigated in treatments of cancer, virus, and parasite infections (i.e., malaria) as well as in crop science.

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ChemInform Abstract: Latent Inhibitors. Part 6. Inhibition of Dihydroorotate Dehydrogenase by Substituted 5‐Benzylhydantoins.

Cited by 2 publications

References 1 publication

Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection

Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection

On Dihydroorotate Dehydrogenases and Their Inhibitors and Uses

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