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 |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Subacute toxicity of all-trans- and 13-cis-isomers of N-ethyl retinamide, N-2-hydroxyethyl retinamide, and N-4-hydroxyphenyl retinamide. | 1983 Sep 15 |
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| Abnormal retinal function associated with fenretinide, a synthetic retinoid. | 1986 Jan |
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| Phase II trial of fenretinide [N-(4-hydroxyphenyl) retinamide] in myelodysplasia: possible retinoid-induced disease acceleration. | 1989 |
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| Regulation of apoptosis induced by the retinoid N-(4-hydroxyphenyl) retinamide and effect of deregulated bcl-2. | 1995 Jan 15 |
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| Retinoid-induced apoptosis and Sp1 cleavage occur independently of transcription and require caspase activation. | 1997 Nov |
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| Comparative ability of ibuprofen and N-(4-hydroxyphenyl)retinamide to inhibit development of rat mammary adenocarcinomas associated with differential inhibition of gene expression of cyclooxygenase isoforms. | 1999 Nov-Dec |
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| Effects of body weight gain reduction resulting from chemopreventive agent treatment on mammary gland morphology. | 2002 |
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| Hydrolysis of 4-HPR to atRA occurs in vivo but is not required for retinamide-induced apoptosis. | 2003 Nov 15 |
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| Identification of retinoid-modulated proteins in squamous carcinoma cells using high-throughput immunoblotting. | 2004 Apr 1 |
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| How retinoids regulate breast cancer cell proliferation and apoptosis. | 2004 Jun |
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| Nuclear retinoid receptors are involved in N-(4-hydroxyphenyl) retinamide (Fenretinide)-induced gene expression and growth inhibition in HL-60 acute myeloid leukemia cells. | 2004 May |
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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 Oct |
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| Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases. | 2005 Dec |
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| Cervical chromosome 9 polysomy: validation and use as a surrogate endpoint biomarker in a 4-HPR chemoprevention trial. | 2005 Dec |
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| BBC3 mediates fenretinide-induced cell death in neuroblastoma. | 2005 Dec 1 |
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| Induction of apoptosis in primary meningioma cultures by fenretinide. | 2005 Feb 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 Jan 20 |
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| [The role of reactive oxygen species in N-[4-hydroxyphenyl] retinamide induced apoptosis in bladder cancer cell lineT24]. | 2005 Jun |
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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 Jun 15 |
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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 Mar 11 |
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| PPAR activation and decreased proliferation in oral carcinoma cells with 4-HPR. | 2005 Nov |
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| Cyclooxygenase-2 protein reduces tamoxifen and N-(4-hydroxyphenyl)retinamide inhibitory effects in breast cancer cells. | 2005 Nov |
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| Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists. | 2005 Oct |
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| 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 Oct 15 |
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| Inhibitory effects of N-(4-hydrophenyl) retinamide on liver cancer and malignant melanoma cells. | 2005 Oct 7 |
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| Retinamide-induced apoptosis in glioblastomas is associated with down-regulation of Bcl-xL and Bcl-2 proteins. | 2005 Sep |
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| Increased level of the p67phox subunit of NADPH oxidase by 4HPR in head and neck squamous carcinoma cells. | 2005 Sep |
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| Chemoprevention of skin carcinogenesis by phenylretinamides: retinoid receptor-independent tumor suppression. | 2006 Feb 1 |
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| The CLN9 protein, a regulator of dihydroceramide synthase. | 2006 Feb 3 |
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| 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 Mar 15 |
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| Fenretinide activity in retinoid-resistant oral leukoplakia. | 2006 May 15 |
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| 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 May 4 |
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| Mechanism of 4-HPR-induced apoptosis in glioma cells: evidences suggesting role of mitochondrial-mediated pathway and endoplasmic reticulum stress. | 2006 Oct |
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| Comparing the effect of ATRA, 4-HPR, and CD437 in bladder cancer cells. | 2006 Sep 1 |
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| 4-HPR modulates gene expression in ovarian cells. | 2006 Sep 1 |
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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 Apr 10 |
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| Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth. | 2007 Apr 23 |
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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 Feb |
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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 Mar |
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| Role of Noxa in p53-independent fenretinide-induced apoptosis of neuroectodermal tumours. | 2007 Mar |
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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 Feb 1 |
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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 Sep |
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| Induction and intracellular localization of Nur77 dictate fenretinide-induced apoptosis of human liver cancer cells. | 2010 Apr 1 |
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| Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. | 2010 Feb 26 |
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| HIF-1α-dependent autophagy protects HeLa cells from fenretinide (4-HPR)-induced apoptosis in hypoxia. | 2010 Nov |
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| Targeting GRP78 to enhance melanoma cell death. | 2010 Oct |
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| Fenretinide derivatives act as disrupters of interactions of serum retinol binding protein (sRBP) with transthyretin and the sRBP receptor. | 2011 Jul 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 Mar |
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| Receptor tyrosine kinase inhibitors and cytotoxic drugs affect pleural mesothelioma cell proliferation: insight into EGFR and ERK1/2 as antitumor targets. | 2011 Nov 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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236106
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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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m5295
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ACTIVE MOIETY
