Ribonucleotide reductase rnr catalyzes the conversion of ribonucleotides to deoxyribonucleotides dntps, which are necessary for both replicative and repair dna synthesis. Citeseerx document details isaac councill, lee giles, pradeep teregowda. We hypothesized that other genes in the dntp supply system would compensate for such p53r2 losses and looked for this in our own data and in data of the gene expression omnibus geo. The development of rr inhibitors has necessarily advanced along with our. Therapeutics program dtp nci diversity set freeforpublic access. Rnr1 and rnr2, which form heterodimeric tetramers and a unique feature of note is the. Evaluating the therapeutic potential of a nonnatural nucleotide that inhibits human ribonucleotide reductase. Despite the apparent clinical benefits of highdose cytarabine arac over lower dose arac in acute myeloid leukemia aml therapy, the mechanism behind highdose arac therapy remains uncertain. Phase i study of gti2040, an antisense to ribonucleotide. Ribonucleotide reductase inhibitor 3ap induces oncogenic. Ribonucleotide reductase rnr catalyzes reduction of the four different. Nheterocyclic carboxaldehyde thiosemicarbazones derivatives exhibit anticancer activity by inhibiting ribonucleotide reductase rnr enzyme was considered for the present computational study. Next, we further characterized the mechanism of inhibition using. The p53 gene is frequently inactivated in human cancers.
Here, a potent small interfering rna sirna duplex against the m2 subunit of rr rrm2 is developed and shown to reduce the growth potential of cancer cells both in vitro and in vivo. Methylhydroxylamine as an efficacious antibacterial agent. This antineoplastic or immunomodulatory drug article is a stub. One major advantage of coh29 over other rnr inhibitors in development, such. Ribonucleotide reductase, cancer, inhibitor, pancreatic. Meng lou, qian liu, guoping ren, jiling zeng, xueping xiang, yongfeng ding, qinghui lin, tingting zhong, xia liu, lijun zhu, hongyan qi, jing shen, haoran li, jimin shao. Rare side effects include nausea, rashes, mouth ulcers, and hand or leg ulcers. Cyclin fmediated degradation of ribonucleotide reductase. The cincinnati library consisting of 350,000 compounds was screened in silico using the schrodinger software. Evaluating the therapeutic potential of a nonnatural. Pdf ribonucleotide reductase rr is a multisubunit enzyme responsible for the reduction of ribonucleotides to their corresponding.
While some researchers have focused on rr inhibitors as chemotherapeutic agents, particularly in hematologic malignancies, some of the most promising data has been generated in the field of radiosensitization. Shao j, zhou b, chu b, yen y 2006 ribonucleotide reductase inhibitors and future drug design. The nucleoside analog gemcitabine, which targets ribonucleotide reductase rr as a diphosphate and dna polymerases as a triphosphate, is the standard firstline treatment in patients with pancreatic cancer. In this study, a lcmsbased method was carried out to investigate the metabolic alteration of ribonucleotide and deoxyribonucleotide in human promyelocytic leukemia cells hl60 after treatment. Modulation of the ribonucleotide reductaseantimetabolite drug interaction in cancer cell lines. Hydroxyurea, also called hydroxycarbamide, nh2conhoh, inhibit ribonucleotidediphosphate reductase. Dna replication stress is an inefficient dna synthesis process that leads replication forks to progress slowly or stall. Coh29 n 43,4dihydroxyphenyl5phenylthiazol2yl3,4dihydroxybenzamide, a novel antimetabolite drug developed at city of hope cancer center, has anticancer activity that stems primarily from the inhibition of human ribonucleotide reductase rnr. Ribonucleotide reductase rr is the enzyme that catalyses the ratelimiting step in dna synthesis, the production of deoxynucleotides. The novel ribonucleotide reductase inhibitor coh29 inhibits dna repair in vitro. So, homology modeling contributes much in the drug discovery. Ribonucleotide reductase rr, the rate limiting enzyme in the synthesis and repair of dna, has been studied as a target for inhibition in the treatment of cancer for many years. Potent sirna inhibitors of ribonucleotide reductase. This key enzyme in deoxyribonucleotide biosynthesis is the target of established clinical agents such as hydroxyurea and gemcitabine.
Ribonucleotide reductase rnr, also known as ribonucleotide diphosphate reductase rndp, is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. Here we have isolated a p53inducible gene, p53r2, by using differential display to examine messenger rnas in a cancerderived human cell. In a future subject, it will be shown that two of these compounds specifically inhibit the m1 subunit of the ribonucleotide reductase enzyme and it will also be shown that 2halogen substituted adenosine derivatives are especially potent inhibitor of rnr. Design and synthesis of potential ribonucleotide reductase enzyme rnr inhibitors as antileukemic andor antiviral 2. Ribonucleotide reductase inhibitors and future drug design volume. Ribonucleotide reductase rnr catalyzes reduction of the four different ribonucleotides to their corresponding deoxyribonucleotides and is the ratelimiting enzyme in dna synthesis. It is therefore an excellent target for cancer chemotherapy. Future work will involve the study of the structureactivity relationship. This enzyme, in presence of iron and reduced hs groups converts monophosphate and diphosphate ribonucleotides adenosine, guanosine, cytidine into the corresponding deoxyribonucleotides. Ribonucleotide reductase is composed of two subunits. Rnr is a wellestablished target for the antiproliferative drugs gemzar and hydrea, for antisense therapy, and in combination chemotherapies.
Sorafenib inhibits ribonucleotide reductase regulatory. Ribonucleotide reductase rnr is a key enzyme in dna replication that acts by converting ribonucleotides into the corresponding deoxyribonucleotides, which are the building blocks of dna replication and repair. The results of this study will lead to the design of future generations of. Three classes of rnrs employ different mechanisms for the generation of the protein radical. Ribonucleotide reductase inhibition assays and mechanism. Ribonucleotide reductase rnr is the key enzyme in the biosynthesis of deoxyribonucleotides. Discovery of antimicrobial ribonucleotide reductase. Cellbased assay ribonucleotide reductase inhibition. Ribonucleotide reductase rr is a therapeutic target for dna replicationdependent diseases such as cancer. A smallmolecule blocking ribonucleotide reductase holoenzyme. Ribonucleotide reductases rnrs transform rna building blocks to dna building blocks by catalyzing the substitution of the 2. Didox, a ribonucleotide reductase inhibitor, induces. Identification of nonnucleoside human ribonucleotide reductase. Ribonucleotide reductase rnr, containing regulatory hrrm1.
Deoxyribonucleotides in turn are used in the synthesis of dna. The novel ribonucleotide reductase inhibitor coh29 inhibits dna. The search for anticancer drugs continues to be greatly pursued. A nucleoside metabolic inhibitor used as adjunct therapy in the treatment of certain types of ovarian cancer, nonsmall cell lung.
The novel ribonucleotide reductase inhibitor coh29. Yen y 2006 ribonucleotide reductase inhibitors and future drug design. Ribonucleotide reductase inhibitors and future drug. The expression of ribonucleotide reductase m2 in the. We performed a phase i dose escalation trial of arac combined with gti2040, a 20mer antisense oligonucleotide. Investigating synergy between ribonucleotide reductase inhibitors and cmv antivirals a thesis submitted in partial fulfillment of the requirements for the degree of master of science at virginia commonwealth university. Furthermore, in the near future, integration of homology modeling with other computer. Drugs targeting rr are mainly nucleoside in nature. Structureguided design of anticancer ribonucleotide reductase. Potent competitive inhibition of human ribonucleotide. Design and synthesis of potential ribonucleotide reductase.
Potent competitive inhibition of human ribonucleotide reductase by a. Provided herein are novel compounds that inhibit ribonucleotide reductase rr by binding to rrm2 and interfering with the activity of the rrm1rrm2 holoenzyme. Inhibition of dna synthesis and ribonucleotide reductase activity by chl hct116 cells were pretreated with chl and pulse. The key role of rr in dna synthesis and cell growth control has made it an important target for anticancer therapy. Structureguided design of anticancer ribonucleotide.
Two main factors that cause replication stress are alterations in pools of deoxyribonucleotide dntp precursors required for dna synthesis and changes in the activity of proteins required for synthesis of dntps. Inhibition of ribonucleotide reductase reduces the availability of the endogenous pool of deoxycytidine and may increase cytarabine arac cytotoxicity. The emergence of multidrugresistant bacteria has encouraged vigorous efforts to develop antimicrobial agents with new mechanisms of action. Rr catalyses the ratedetermining step of dntp synthesis by removing the 2. Structureguided design of anticancer ribonucleotide reductase inhibitors article pdf available in journal of enzyme inhibition and medicinal chemistry 341. Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance of drug targets. Funding sources had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Hydroxamates as ribonucleotide reductase inhibitors. Development of ribonucleotide reductase inhibitors. The expression of ribonucleotide reductase m2 in the carcinogenesis of uterine cervix and its relationship with clinicopathological characteristics and prognosis of cancer patients.
Using affinity purifications and mass spectrometry, we identified rrm2 the ribonucleotide reductase family member 2 as an interactor of the fbox protein cyclin f. We performed a phase i dose escalation trial of arac combined with gti2040, a 20mer antisense oligonucleotide shown in preclinical studies to decrease levels of the r2 subunit of ribonucleotide reductase, to determine the maximum. Cellular assay for rnr inhibitors this assay has been specially tailored to validate ribonucleotide reductase rnr inhibition by a given compound in cultured cells. Ribonucleotide reductase, structure and function, inhibitors, classification, mechanism of action, clinical trial and application, drug discovery. A novel ligandbinding pocket on the rnr small subunit rrm2 near. Ribonucleotide reductase inhibitors and future drug design. Gemcitabine is a billiondollar drug used as a front line treatment of.
The key role of rr in dna synthesis and cell growth control has made it an important. Ribonucleotide diphosphate reductase inhibitors pharmacorama. After incubation of cultured cells with the inhibitor, this high performance liquid chromatography analysis of nucleotides consists in. Sorafenib inhibits ribonucleotide reductase regulatory subunit m2 rrm2 in hepatocellular carcinoma cells. Surprisingly, few novel drugs that target rnr have emerged, partly. Plots of measured vs predicted concentrations were plotted in origin graphing software. Modulation of the ribonucleotide reductaseantimetabolite.
City of hope national medical center, 1500 east duarte road, duarte, ca 91010, usa. Pdf ribonucleotide reductase inhibitors and future drug design. There are three classes of rnrs classes i iii, but only class i are present in eukaryotes. However, its cytotoxicity to normal dividing tissues leads to unwanted side effects.
The enzyme has thus an attractive target for chemotherapies that fight proliferationbased diseases. For drug combination experiments, the ic50 values obtained from single drug assays were used to design the experiments, and the cell viability assays were performed as described above. Human ribonucleotide reductase hrr is a ubiquitous multisubunit enzyme that is crucial for cell division and dna repair14. Discovery of antimicrobial ribonucleotide reductase inhibitors by. Ribonucleotide reductase rr is a multisubunit enzyme responsible for the reduction of ribonucleotides to their corresponding deoxyribonucleotides, which are building blocks for dna replication and repair. Homology modeling is used in determining 3d structures of proteins, and it has many applications in the drug discovery process. Induction of autophagy reduced cellular levels of rrm2, a subunit of ribonucleotide reductase rr, the rate limiting enzyme in the production of deoxyribonucleotide triphosphates. Rr activity is markedly elevated in tumour tissue and is crucial for cell division. These groups are showed to be active as ribonucleotide reductase inhibitors and their incorporation results in a bioconjugate. Ribonucleotide reductase rr is a ubiquitous multisubunit enzyme that. Qsar and pharmacophore analysis of thiosemicarbazone. This chapter presents the progress in the design and discovery of hydroxamic acids acting as ribonucleotide reductase rr inhibitors.
Ribonucleotide reductase rnr is an attractive target for anticancer agents. Understanding the mechanism for ribonucleotide reductase. Loss of the transcription factor p53 implies mrna losses of target genes such as the p53r2 subunit of human ribonucleotide reductase rnr. Ohgroup of a ribonucleotide with a hydrogen by a mechanism involving protein radicals.
A smallmolecule blocking ribonucleotide reductase holoenzyme formation inhibits cancer cell growth and overcomes drug resistance bingsen zhou, leila su, shuya hu, weidong hu, m. To test this hypothesis, we treated breast cancer mdamb231 cells with tamoxifen tmx, which induces autophagy through an estrogen receptorindependent pathway. Ribonucleotide reductase inhibitors are a family of anticancer drugs that interfere with the growth of tumor cells by blocking the formation of deoxyribonucleotides building. Ribonucleotide reductase assay was performed as previously described, with slight modification. In the absence of chl treatment, most of the brdu labeling 96% was associated with the s. Ribonucleotide reductase inhibitors and fut ure drug design current cancer drug target s, 2006, vol. Ribonucleotide reductase inhibitor 3ap induces oncogenic virus infected cell death and represses tumor growth.
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