In several T-ALL cell lines, fenretinide (4-HPR) exhibits both short-term and long-term anticancer action. In CCRF-CEM leukemia cells, fenretinide suppresses DES activity in a dose- and time-dependent manner, increasing endogenous cellular dhCer levels in the process. In CCRF-CEM and Jurkat cells, fenretinide (3 μM) causes an accumulation of dhCer [1]. Insulin signaling is protected by fenretinide's inhibition of ceramide. Insulin-stimulated glucose absorption is prevented from decreasing by lipids when fenretinide is present [2]. At concentrations above 1 microM, fenretinide decreases OVCAR-5 cell survival and proliferation; at 10 microM, it suppresses growth by 70–90%. After three days of preincubation, fenretinide (1 microM) dramatically reduced OVCAR-5 invasion. After being exposed to 1 µM 4-HPR, endothelial cells did not form tubes; instead, they produced tiny cell aggregates [4].

In male C57Bl/6 mice fed a high-fat diet, fenretinide (4-HPR) (10 mg/kg, ip) selectively prevents the build-up of ceramides. Tests for insulin and glucose tolerance show that fenretinide treatment increases insulin sensitivity and glucose tolerance [2]. The addition of 25 mg/kg ketoconazole to fenretinide raised the plasma levels of 4-HPR in NOD/SCID mice [3].

Metabolism / Metabolites
Known metabolites of fenritinib include (2S,3S,4S,5R)-6-[4-[[(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)non-2,4,6,8-tetraenoyl]amino]phenoxy]-3,4,5-trihydroxyoxacyclohexane-2-carboxylic acid.

[1]. Dihydroceramide accumulation and reactive oxygen species are distinct and nonessential events in 4-HPR-mediated leukemia cell death. Biochemistry and Cell Biology (2012), 90(2), 209-223.

[2]. Fenretinide Prevents Lipid-induced Insulin Resistance by Blocking Ceramide Biosynthesis. Journal of Biological Chemistry (2012), 287(21), 17426-17437.

[3]. Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure. Br J Pharmacol. 2011 Jul;163(6):1263-75.

[4]. Action of fenretinide (4-HPR) on ovarian cancer and endothelial cells. Anticancer Res. 2005 Jan-Feb;25(1A):249-53.

4-Hydroxyphenyl retinamide is a retinoid formed by the condensation of the carboxyl group of all-trans retinoic acid and the aniline group of 4-hydroxyaniline. It is a synthetic retinoid agonist with antiproliferative, antioxidant, and anticancer activities and a long in vivo half-life. Its apoptotic mechanism appears to differ from that of "classic" retinoids. It possesses antitumor and antioxidant effects. It is a retinoid and monocarboxylic acid amide functionally related to all-trans retinoic acid. A synthetic retinoid, it can be taken orally for the prevention of prostate cancer and for the prevention of contralateral breast cancer in women at risk. It also has antitumor activity. Fentrinib is an orally effective synthetic phenylretinamide retinoid (vitamin A) analog with potential antitumor and chemopreventive activities. Fentrinib binds to and activates retinoic acid receptors (RARs), thereby inducing differentiation and apoptosis in certain tumor cell types. The drug can also inhibit tumor growth by modulating angiogenesis-related growth factors and their receptors, exhibiting retinoid receptor-independent apoptotic properties. (NCI04)
A synthetic retinoid, taken orally for the prevention of prostate cancer and also for the prevention of contralateral breast cancer in women at risk. It is also an effective anti-tumor drug.
Drug Indications

Studied for the treatment of macular degeneration.
Mechanism of Action

Fentrinib inhibits the growth of various human cancer cell lines through retinoic acid receptor-dependent and non-retinoic acid-dependent mechanisms.¹In vivo, fenritinib selectively accumulates in mammary tissue, particularly effectively inhibiting the development of breast cancer in rats.¹An important characteristic of fenritinib is that it inhibits cell growth by inducing apoptosis rather than differentiation, which is quite different from the mechanism of action of vitamin A.¹Unlike tamoxifen, which only inhibits estrogen receptor (ER)-positive tumors, fenritinib can induce apoptosis in both ER-positive and ER-negative breast cancer cell lines.²All these properties make fenritinib an ideal candidate drug for the treatment of breast cancer. Chemoprophylaxis.

C26H33NO2

391.5457

391.251

65646-68-6

5288209

Light yellow to yellow solid powder

1.1±0.1 g/cm3

597.6±42.0 °C at 760 mmHg

162-163°C

315.2±27.9 °C

0.0±1.8 mmHg at 25°C

1.607

7.41

2

2

6

29

726

0

CC1=C(C(CCC1)(C)C)/C=C/C(=C/C=C/C(=C/C(=O)NC2=CC=C(C=C2)O)/C)/C

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+

(2E,4E,6E,8E)-N-(4-hydroxyphenyl)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenamide

4-HPR McNR-1967 McNR1967 McNR 1967 HPR Fenretinide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 130 mg/mL (~332.01 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.38 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.38 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.38 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)