Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C10H12FN3O4 |
Molecular Weight | 257.2184 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 3 / 3 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
NC1=NC(=O)N(C=C1)[C@H]2[C@H](O)[C@H](O)C(CO)=C2F
InChI
InChIKey=QLLGKCJUPWYJON-HLTSFMKQSA-N
InChI=1S/C10H12FN3O4/c11-6-4(3-15)8(16)9(17)7(6)14-2-1-5(12)13-10(14)18/h1-2,7-9,15-17H,3H2,(H2,12,13,18)/t7-,8-,9+/m1/s1
Molecular Formula | C10H12FN3O4 |
Molecular Weight | 257.2184 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 3 / 3 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
DescriptionCurator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/24048768 | http://investors.rexahn.com/releasedetail.cfm?releaseid=992786
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/24048768 | http://investors.rexahn.com/releasedetail.cfm?releaseid=992786
Fluorocyclopentenylcytosine (RX-3117) is a novel small molecule nucleoside compound that is incorporated into DNA or RNA of cancer cells and inhibits both
DNA and RNA synthesis which induces apoptotic cell death of tumor cells. Fluorocyclopentenylcytosine also mediates the down-regulation of DNA
methyltransferase 1 (DNMT1), an enzyme responsible for the methylation of cytosine residues on newly synthesized DNA and
also a target for anticancer therapies. Preclinical studies have shown Fluorocyclopentenylcytosine to be effective in both inhibiting the growth of
various human cancer xenograft models, including colon, lung, renal and pancreas, as well as overcoming chemotherapeutic
drug resistance.
Fluorocyclopentenylcytosine has demonstrated a broad spectrum anti-tumor activity against 50 different human cancer cell lines and efficacy in 12
different mouse xenograft models. The efficacy in the mouse xenograft models was superior to that of gemcitabine. In addition,
in human cancer cell lines made resistant to the anti-tumor effects of gemcitabine, Fluorocyclopentenylcytosine still retains its full anti-tumor
activity.
In August 2012, Rexahn reported the completion of an exploratory Phase I clinical trial of Fluorocyclopentenylcytosine in cancer patients conducted
in Europe, to investigate the oral bioavailability, safety and tolerability of the compound. In this study, oral administration of Fluorocyclopentenylcytosine demonstrated an oral bioavailability of 34-58% and a plasma half-life (T1/2) of 14 hours. In addition, Fluorocyclopentenylcytosine was safe
and well tolerated in all subjects throughout the dose range tested. Fluorocyclopentenylcytosine is in phase I/II clinical trials by Rexahn for the treatment of bladder cancer and pancreatic cancer. This compound was granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with pancreatic cancer in September 2014.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL1993 |
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Target ID: CHEMBL612540 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24048768 |
0.9 µM [IC50] | ||
Target ID: CHEMBL614004 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24048768 |
0.4 µM [IC50] | ||
Target ID: map03030 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
PubMed
Title | Date | PubMed |
---|---|---|
Metabolism, mechanism of action and sensitivity profile of fluorocyclopentenylcytosine (RX-3117; TV-1360). | 2013 Dec |
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A novel cytidine analog, RX-3117, shows potent efficacy in xenograft models, even in tumors that are resistant to gemcitabine. | 2014 Dec |
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The Cytidine Analog Fluorocyclopentenylcytosine (RX-3117) Is Activated by Uridine-Cytidine Kinase 2. | 2016 |
Patents
Sample Use Guides
Patients in the trial will be receiving a 700 mg daily oral dose of Fluorocyclopentenylcytosine (RX-3117), five times weekly for three weeks in a 28 day cycle for up to eight treatment cycles, or until their disease progresses.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24048768
In sensitive U937 cells 1 uM RX-3117 resulted in 90% inhibition of RNA synthesis but 100 uM RX-3117 was required in A2780 and CCRF-CEM cells.
Substance Class |
Chemical
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EU-Orphan Drug |
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447314
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FLUOROCYCLOPENTENYLCYTOSINE
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PRIMARY | MedKoo Cat#: 206092Name: RX-3117CAS#: 865838-26-2Chemical Formula: C10H12FN3O4Exact Mass: 257.08118Molecular Weight: 257.22Elemental Analysis: C, 46.69; H, 4.70; F, 7.39; N, 16.34; O, 24.88 | ||
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ACTIVE MOIETY |
Cytadine analogue RX-3117: An orally available small molecule and nucleoside antimetabolite with potential antineoplastic activity. Upon administration, the cytidine analogue RX-3117 is taken up by cells through a carrier-mediated transporter, phosphorylated by uridine cytidine kinase (UCK) and then further phosphorylated to its diphosphate (RX-DP) and triphosphate forms (RX-TP). The triphosphate form is incorporated into RNA and inhibits RNA synthesis. The diphosphate RX-DP is reduced by ribonucleotide reductase (RR) to dRX-DP its triphosphate form (dRX-TP) is incorporated into DNA. In addition, RX-3117 also inhibits DNA methyltransferase 1 (DNMT1). This eventually leads to cell cycle arrest and the induction of apoptosis. UCK is the rate-limiting enzyme in the pyrimidine-nucleotide salvage pathway. Check for active clinical trials using this agent. (NCI Thesaurus)
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ACTIVE MOIETY |
A novel cytidine analog fluorocyclopentenylcytosine (RX-3117, TV-1360) was characterized for its cytotoxicity in a 59-cell line panel and further characterized for cytotoxicity, metabolism and mechanism of action in 15 additional cancer cell lines, including gemcitabine-resistant variants. In both panels sensitivity varied 75-fold (IC50: 0.4- > 30 .MU.M RX-3117). RX-3117 showed a different sensitivity profile compared to cyclopentenyl-cytosine (CPEC) and azacytidine, substrates for uridine-cytidine-kinase (UCK). Dipyridamole, an inhibitor of the equilibrative-nucleoside-transporter protected against RX-3117. Uridine and cytidine protected against RX-3117, but deoxycytidine (substrate for deoxycytidine-kinase (dCK)) not, although it protected against gemcitabine, demonstrating that RX-3117 is a substrate for UCK and not for dCK. UCK activity was abundant in all cell lines, including the gemcitabine-resistant variants.
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ACTIVE MOIETY |
RX-3117 has shown broad spectrum anti-tumor activity against over 100 different human cancer cell lines and efficacy in 17 different mouse xenograft models. In preclinical mouse xenograft studies, RX-3117 demonstrated superior efficacy to gemcitabine. In addition, RX-3117 retained its full anti-tumor activity in human cancer cell lines made resistant to the anti-tumor effects of gemcitabine, supporting a unique, highly-targeted mechanism of action.
An exploratory Phase I clinical trial of RX-3117 showed that oral administration of a 50 mg dose of RX-3117 achieved oral bioavailability of 56% and a plasma half-life (T1/2) of 14 hours. In addition, RX-3117 appeared to be safe and well tolerated in all subjects throughout the dose range tested.
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