Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C26H33NO2 |
| Molecular Weight | 391.5457 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 4 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CC(\C=C\C1=C(C)CCCC1(C)C)=C/C=C/C(C)=C/C(=O)NC2=CC=C(O)C=C2
InChI
InChIKey=AKJHMTWEGVYYSE-FXILSDISSA-N
InChI=1S/C26H33NO2/c1-19(11-16-24-21(3)10-7-17-26(24,4)5)8-6-9-20(2)18-25(29)27-22-12-14-23(28)15-13-22/h6,8-9,11-16,18,28H,7,10,17H2,1-5H3,(H,27,29)/b9-6+,16-11+,19-8+,20-18+
Fenretinide (4-HPR) is an orally-active synthetic phenylretinamide analogue of retinol (vitamin A) with potential antineoplastic and chemopreventive activities. Fenretinide binds to and activates retinoic acid receptors (RARs), thereby inducing cell differentiation and apoptosis in some tumor cell types. This agent also inhibits tumor growth by modulating angiogenesis-associated growth factors and their receptors and exhibits retinoid receptor-independent apoptotic properties. Phase III clinical trial data has suggested that fenretinide reduces breast cancer relapse in pre-menopausal women. Fenretinide is the most studied retinoid in breast cancer chemoprevention clinical trials due to its selective accumulation in breast tissue and its favorable toxicological profile. This agent showed a significative reduction of the incidence of second breast tumors in premenopausal women confirmed after 15-year followups. Fenretinide, a drug being developed by Sirion Therapeutics, slowed the progression of advanced dry age-related macular degeneration (AMD) by 45 percent for people receiving a higher dose of the treatment in a Phase II clinical trial. Sirion has been granted a Fast Track designation for the treatment by the FDA. Fenretinide is in phase II clinical trials for the treatment of B-cell lymphoma, chronic lymphocytic leukemia. It is also in phase I clinical trials for the treatment of cystic fibrosis.
CNS Activity
Curator's Comment: Animal studies suggest that fenretinide can cross the blood-brain barrier, probably due to its lipophilicity. Clinical trials from patients with glioma indicated that 4-HPR is able to cross the blood brain barrier (BBB), suggesting its potential for the treatment of central nervous system tumors.
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
| 220.0 nM [EC50] | |||
Target ID: CHEMBL2021749 |
2.32 µM [IC50] | ||
Target ID: CHEMBL3100 |
56.0 µM [IC50] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| 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 |
|---|---|---|---|---|
7.3 μM EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16034523 |
1800 mg/m² 2 times / day multiple, oral dose: 1800 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: [NO STEREO] NSC-LSC-1|[NO STEREO] PACLITAXEL |
FENRETINIDE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
60.3 μM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16034523 |
1800 mg/m² 2 times / day multiple, oral dose: 1800 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: [NO STEREO] NSC-LSC-1|[NO STEREO] PACLITAXEL |
FENRETINIDE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
14.5 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16034523 |
1800 mg/m² 2 times / day multiple, oral dose: 1800 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: [NO STEREO] NSC-LSC-1|[NO STEREO] PACLITAXEL |
FENRETINIDE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Receptor tyrosine kinase inhibitors and cytotoxic drugs affect pleural mesothelioma cell proliferation: insight into EGFR and ERK1/2 as antitumor targets. | 2011-11-15 |
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| Fenretinide derivatives act as disrupters of interactions of serum retinol binding protein (sRBP) with transthyretin and the sRBP receptor. | 2011-07-14 |
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| Enrichment of Nur77 mediated by retinoic acid receptor β leads to apoptosis of human hepatocellular carcinoma cells induced by fenretinide and histone deacetylase inhibitors. | 2011-03 |
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| HIF-1α-dependent autophagy protects HeLa cells from fenretinide (4-HPR)-induced apoptosis in hypoxia. | 2010-11 |
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| Targeting GRP78 to enhance melanoma cell death. | 2010-10 |
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| Induction and intracellular localization of Nur77 dictate fenretinide-induced apoptosis of human liver cancer cells. | 2010-04-01 |
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| Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. | 2010-02-26 |
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| Pharmacokinetics of oral fenretinide in neuroblastoma patients: indications for optimal dose and dosing schedule also with respect to the active metabolite 4-oxo-fenretinide. | 2008-09 |
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| p-Dodecylaminophenol derived from the synthetic retinoid, fenretinide: antitumor efficacy in vitro and in vivo against human prostate cancer and mechanism of action. | 2008-02-01 |
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| Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth. | 2007-04-23 |
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| Targeting homeostatic mechanisms of endoplasmic reticulum stress to increase susceptibility of cancer cells to fenretinide-induced apoptosis: the role of stress proteins ERdj5 and ERp57. | 2007-04-10 |
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| Fenretinide up-regulates DR5/TRAIL-R2 expression via the induction of the transcription factor CHOP and combined treatment with fenretinide and TRAIL induces synergistic apoptosis in colon cancer cell lines. | 2007-03 |
|
| Role of Noxa in p53-independent fenretinide-induced apoptosis of neuroectodermal tumours. | 2007-03 |
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| Increased expression of the MGMT repair protein mediated by cysteine prodrugs and chemopreventative natural products in human lymphocytes and tumor cell lines. | 2007-02 |
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| Anti-proliferative activity of fenretinide in human hepatoma cells in vitro and in vivo. | 2007-01 |
|
| N-(4-hydroxyphenyl)retinamide induces apoptosis in human retinal pigment epithelial cells: retinoic acid receptors regulate apoptosis, reactive oxygen species generation, and the expression of heme oxygenase-1 and Gadd153. | 2006-12 |
|
| Fenretinide-induced neuronal differentiation of ARPE-19 human retinal pigment epithelial cells is associated with the differential expression of Hsp70, 14-3-3, pax-6, tubulin beta-III, NSE, and bag-1 proteins. | 2006-11-01 |
|
| Regulation of lipocalin-2 gene by the cancer chemopreventive retinoid 4-HPR. | 2006-10-01 |
|
| Mechanism of 4-HPR-induced apoptosis in glioma cells: evidences suggesting role of mitochondrial-mediated pathway and endoplasmic reticulum stress. | 2006-10 |
|
| Comparing the effect of ATRA, 4-HPR, and CD437 in bladder cancer cells. | 2006-09-01 |
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| 4-HPR modulates gene expression in ovarian cells. | 2006-09-01 |
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| Retinoids activate the RXR/SXR-mediated pathway and induce the endogenous CYP3A4 activity in Huh7 human hepatoma cells. | 2006-07 |
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| Fenretinide activity in retinoid-resistant oral leukoplakia. | 2006-05-15 |
|
| N-(4-hydroxyphenyl)retinamide-induced apoptosis triggered by reactive oxygen species is mediated by activation of MAPKs in head and neck squamous carcinoma cells. | 2006-05-04 |
|
| 4-oxo-fenretinide, a recently identified fenretinide metabolite, induces marked G2-M cell cycle arrest and apoptosis in fenretinide-sensitive and fenretinide-resistant cell lines. | 2006-03-15 |
|
| Clinical trials with retinoids for breast cancer chemoprevention. | 2006-03 |
|
| The CLN9 protein, a regulator of dihydroceramide synthase. | 2006-02-03 |
|
| Chemoprevention of skin carcinogenesis by phenylretinamides: retinoid receptor-independent tumor suppression. | 2006-02-01 |
|
| Cholecalciferol (vitamin D3) and the retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) are synergistic for chemoprevention of prostate cancer. | 2006 |
|
| BBC3 mediates fenretinide-induced cell death in neuroblastoma. | 2005-12-01 |
|
| Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases. | 2005-12 |
|
| Cervical chromosome 9 polysomy: validation and use as a surrogate endpoint biomarker in a 4-HPR chemoprevention trial. | 2005-12 |
|
| PPAR activation and decreased proliferation in oral carcinoma cells with 4-HPR. | 2005-11 |
|
| Cyclooxygenase-2 protein reduces tamoxifen and N-(4-hydroxyphenyl)retinamide inhibitory effects in breast cancer cells. | 2005-11 |
|
| N-(4-hydroxyphenyl)retinamide inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of I(kappa)B(alpha) kinase and nuclear factor-kappaB-regulated gene products. | 2005-10-15 |
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| Inhibitory effects of N-(4-hydrophenyl) retinamide on liver cancer and malignant melanoma cells. | 2005-10-07 |
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| Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists. | 2005-10 |
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| Retinamide-induced apoptosis in glioblastomas is associated with down-regulation of Bcl-xL and Bcl-2 proteins. | 2005-09 |
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| Increased level of the p67phox subunit of NADPH oxidase by 4HPR in head and neck squamous carcinoma cells. | 2005-09 |
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| The transforming growth factor-beta family members bone morphogenetic protein-2 and macrophage inhibitory cytokine-1 as mediators of the antiangiogenic activity of N-(4-hydroxyphenyl)retinamide. | 2005-06-15 |
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| [The role of reactive oxygen species in N-[4-hydroxyphenyl] retinamide induced apoptosis in bladder cancer cell lineT24]. | 2005-06 |
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| Expression of gastrointestinal glutathione peroxidase is inversely correlated to the presence of hepatitis C virus subgenomic RNA in human liver cells. | 2005-03-11 |
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| Induction of apoptosis in primary meningioma cultures by fenretinide. | 2005-02-15 |
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| Induction of reactive oxygen species renders mutant and wild-type K-ras pancreatic carcinoma cells susceptible to Ad.mda-7-induced apoptosis. | 2005-01-20 |
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| Breast cancer progression in MCF10A series of cell lines is associated with alterations in retinoic acid and retinoid X receptors and with differential response to retinoids. | 2004-10 |
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| Retinoid-induced apoptosis and Sp1 cleavage occur independently of transcription and require caspase activation. | 1997-11 |
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| Regulation of apoptosis induced by the retinoid N-(4-hydroxyphenyl) retinamide and effect of deregulated bcl-2. | 1995-01-15 |
|
| Phase II trial of fenretinide [N-(4-hydroxyphenyl) retinamide] in myelodysplasia: possible retinoid-induced disease acceleration. | 1989 |
|
| Abnormal retinal function associated with fenretinide, a synthetic retinoid. | 1986-01 |
|
| Subacute toxicity of all-trans- and 13-cis-isomers of N-ethyl retinamide, N-2-hydroxyethyl retinamide, and N-4-hydroxyphenyl retinamide. | 1983-09-15 |
Sample Use Guides
Individuals participating in the Phase II study received either one of two oral doses of fenretinide — 300 mg or 100 mg. While both doses slowed the growth of the harmful lesions associated with advanced dry AMD (also known as geographic atrophy), the higher dose was more effective.
Route of Administration:
Oral
In Vitro Use Guide
Curator's Comment: Fenretinide inhibits OVCAR-5 cell proliferation and viability at concentrations higher than 1 uM, with 70-90% growth inhibition at 10 microM. Fenretinide (1 uM) significantly inhibits OVCAR-5 invasion after 3 days preincubation. Endothelial cells treated with 1 uM 4-HPR fails to form tubes, but forms small cellular aggregates. https://www.ncbi.nlm.nih.gov/pubmed/15816545
At the measured IC(50) of 10 uM, 4-HPR led to a 44-68% reduction in [(3)H]thymidine incorporation, a >3-fold increase in de novo ceramide levels, a 2.7-fold increase in ROS, and minor increases in markers of apoptosis in human pancreatic cancer cell lines.
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FDA ORPHAN DRUG |
409913
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FDA ORPHAN DRUG |
236106
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74193
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FDA ORPHAN DRUG |
209805
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NCI_THESAURUS |
C804
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FDA ORPHAN DRUG |
303210
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FDA ORPHAN DRUG |
621117
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FDA ORPHAN DRUG |
404013
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EU-Orphan Drug |
EU/3/06/427
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FENRETINIDE
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m5295
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187EJ7QEXL
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ACTIVE MOIETY
