Details
Stereochemistry | ACHIRAL |
Molecular Formula | C5H6BrN3O5 |
Molecular Weight | 268.022 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
[O-][N+](=O)C1(CN(C1)C(=O)CBr)[N+]([O-])=O
InChI
InChIKey=JODKFOVZURLVTG-UHFFFAOYSA-N
InChI=1S/C5H6BrN3O5/c6-1-4(10)7-2-5(3-7,8(11)12)9(13)14/h1-3H2
RRX-001, also known as ABDNAZ, is a dinitroazetidine derivative with potential radiosensitizing activity. Upon administration, RRx-001 is able to dilate blood vessels, thereby increasing tumor blood flow and thus improving oxygenation to the tumor site. By increasing oxygen levels, these tumor cells may be more susceptible to radiation therapy. Tumor hypoxia is correlated with tumor aggressiveness, metastasis and resistance to radiotherapy. In mouse models, RRx-001 administered intravenously as a single agent was equipotent to cisplatin while better tolerated. RRx-001 also showed activity as a radiosensitizer in both in vitro and in vivo models. The activity of RRx-001 is thought to be associated with a nucleophilic substitution by circulating thiol compounds and covalent binding of RRx-001 to cysteinyl residues in Hb, followed by the generation of nitrogen oxides. During 2014-2015 EpicentRx has launched Phase 2 trials in brain, colorectal, non-small cell lung, small cell lung and cholangiocarcinoma both alone and in combination. The anti-proliferative effects of RRx-001 are not explainable via a single mechanism. RRx-001 exerts its anti-proliferative effect, at least partially, through interference with glucose 6 phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway, responsible for maintaining adequate levels of the major cellular reductant, NADPH.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL2169726 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26017006 |
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Target ID: CHEMBL5347 |
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Target ID: map04210 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27118403 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
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251.1 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26296952 |
83 mg/m² 1 times / week multiple, intravenous dose: 83 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered: |
RRX-001 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
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1217.5 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26296952 |
83 mg/m² 1 times / week multiple, intravenous dose: 83 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered: |
RRX-001 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
0.45 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26296952 |
83 mg/m² 1 times / week multiple, intravenous dose: 83 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered: |
RRX-001 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
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83 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 83 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 83 mg/m2, 1 times / week Sources: Page: p.5 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.5 |
Disc. AE: Infusion site pain... AEs leading to discontinuation/dose reduction: Infusion site pain (50%) Sources: Page: p.5 |
16.7 mg/m2 1 times / week multiple, intravenous RP2D Dose: 16.7 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 16.7 mg/m2, 1 times / week Sources: Page: p.5 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: Page: p.5 |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Infusion site pain | 50% Disc. AE |
83 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 83 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 83 mg/m2, 1 times / week Sources: Page: p.5 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.5 |
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26296952
Patients with advanced cancer were assigned to receive intravenous infusions of RRx-001 at increasing doses (10 mg/m(2), 16·7 mg/m(2), 24·6 mg/m(2), 33 mg/m(2), 55 mg/m(2), and 83 mg/m(2)) either once or twice-weekly for at least 4 weeks, with at least three patients per dose cohort and allowing a 2-week observation period before dose escalation.
Route of Administration:
Intravenous
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/27232511
RRx-001 and DHEA decreased G6PD activity in a dose dependent way. The G6PD activity for HEP-G2 decreased statiscally from control with RRx-001 and DHEA at 5, 50, and 100 uM, respectively. The G6PD activity for HT-29 decreased statiscally from control with RRx-001 at 5, 50, and 100 uM, and with DHEA at 50 and 100 uM. G6PD activity for HT-29 was statistically decreased for RRx-001 compared to DHEA at 50 and 100 uM. The G6PD activity for CACO-2 decreased statiscally from control with RRx-001 at 5, 50, and 100 uM, and with DHEA at 50 and 100 uM. G6PD activity for CaCO-2 was statistically decreased for RRx-001 compared to DHEA at 50 and 100 uM.
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Classification Tree | Code System | Code | ||
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EU-Orphan Drug |
EU/3/17/1966
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FDA ORPHAN DRUG |
577317
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FDA ORPHAN DRUG |
579817
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FDA ORPHAN DRUG |
737520
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FDA ORPHAN DRUG |
666718
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925206-65-1
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7RPW6SU9SC
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KL-87
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12836
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100000177350
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DB12060
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C97130
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15950826
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ACTIVE MOIETY