Tamibarotene
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MedKoo CAT#: 202780

CAS#: 94497-51-5

Description: Tamibarotene, also known as SY-1425, is an orally active, synthetic retinoid, developed to overcome all-trans retinoic acid (ATRA) resistance, with potential antineoplastic activity. As a specific retinoic acid receptor (RAR) alpha/beta agonist, tamibarotene is approximately ten times more potent than ATRA in inducing cell differentiation and apoptosis in HL-60 (human promyelocytic leukemia) cell lines in vitro. Due to a lower affinity for cellular retinoic acid binding protein (CRABP), tamibarotene may show sustained plasma levels compared to ATRA.

Chemical Structure

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Tamibarotene
CAS# 94497-51-5
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 202780
Name: Tamibarotene
CAS#: 94497-51-5
Chemical Formula: C22H25NO3
Exact Mass: 351.18
Molecular Weight: 351.440
Elemental Analysis: C, 75.19; H, 7.17; N, 3.99; O, 13.66

Price and Availability

Size Price Availability Quantity
200mg USD 150 Ready to ship
500mg USD 330 Ready to ship
1g USD 580 Ready to ship
2g USD 950 Ready to ship
5g USD 1950 Ready to ship
10g USD 3250 Ready to ship
20g USD 5450 Ready to ship
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Synonym: Retinobenzoic acid, Amnoid, AMNOLAKE, Am80, Am 80, Am-80; SY-1425; SY 1425; SY1425; Tamibarotene;

IUPAC/Chemical Name: 4-[(5,5,8,8-Tetramethyl-6,7-dihydronaphthalen-2-yl)carbamoyl]benzoic acid

InChi Key: MUTNCGKQJGXKEM-UHFFFAOYSA-N

InChi Code: InChI=1S/C22H25NO3/c1-21(2)11-12-22(3,4)18-13-16(9-10-17(18)21)23-19(24)14-5-7-15(8-6-14)20(25)26/h5-10,13H,11-12H2,1-4H3,(H,23,24)(H,25,26)

SMILES Code: O=C(O)C1=CC=C(C(NC2=CC=C3C(C)(C)CCC(C)(C)C3=C2)=O)C=C1

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info: Tamibarotene is currently being developed by CytRx Corporation. According to CytRx Corporation's webpages, Tamibarotene was developed to specifically overcome resistance to ATRA. In vitro, tamibarotene is approximately 10 times more potent than ATRA at causing APL cells to differentiate and die. In addition, tamibarotene has a lower affinity for cellular retinoic acid binding protein, or CRABP, which we believe should allow for sustained plasma levels during administration. Tamibarotene does not bind the RAR-α receptor, the major retinoic acid receptor in the dermal epithelium. In clinical studies, the rate of RAS appeared to be low.   Tamibarotene is currently approved in Japan for treatment of recurrent APL. There is a Special Protocol Assessment (SPA) in place with the FDA for a Phase 2 clinical trial, known as STAR-1, which is evaluating the efficacy and safety of tamibarotene as a third-line treatment for APL. The STAR-1 trial is ongoing and currently includes six clinical sites in the U.S. CytRx recently reported that, of the 11 patients enrolled in the STAR-1 trial to date, three (27%) achieved a hematologic complete response, and four (36%) a morphologic leukemia-free state. Based on the preliminary results in the clinical trial for third-line APL, CytRx has announced its intention to work with key opinion leaders to design a clinical trial to evaluate tamibarotene in combination with other agents as a first-line treatment for this cancer. CytRx holds the North American and European rights to tamibarotene as a treatment for APL.  The FDA has granted Orphan Drug Designation for APL and Fast Track Designation for the use of tamibarotene in patients with relapsed or refractory APL following treatment with all-trans retinoic acid (ATRA) and arsenic trioxide. In addition, tamibarotene has been granted orphan medicinal product status by the European Medicines Agency for the treatment of APL. The efficacy of orally-administered tamibarotene was demonstrated in two Phase 2 studies conducted in Japan in a total of 63 Japanese subjects with APL. The overall complete response rate in these subjects was 60%. In subjects experiencing their first relapse, the overall complete response rate was 81%.

Biological target: Tamibarotene is a retinoic acid receptor α/β (RARα/β) agonist, showing high selectivity over RARγ.
In vitro activity: To further investigate the effect of Am80 on apelin promoter activity, VSMCs were co-transfected with GFP–KLF5 expression plasmids and apelin promoter–reporter constructs containing various 5′-deletion fragments. As shown in Figure 4(C), KLF5 overexpression significantly elevated the activities of the apelin promoter of the three different constructs. When Am80 was added, the relative activity of the different constructs further increased. To assess whether the TCE sites in the apelin promoter region were required for Am80-induced apelin expression, the promoter constructs in which the different TCE sites were mutated were co-transfected, respectively, with KLF5 expression plasmid GFP–KLF5. The luciferase activity assay results showed that mutation of site-2 or site-3 did not affect apelin promoter activity and that only the mutation of site-1 blocked the activation of the apelin promoter by KLF5 (Figure 4D). To investigate whether KLF5 bound directly to the TCE sites in Am80-stimulated VSMCs, an oligonucleotide pull-down assay was carried out. As shown in Figure 4(E), KLF5 was bound only to TCE site-1 of the apelin promoter, and Am80 treatment increased its binding. Furthermore, no KLF5 bands were detected when probes containing site-2 or site-3 were used. These results suggest that KLF5 activated apelin transcription by directly binding to site-1 of the apelin promoter. Reference: Biochem J. 2013 Nov 15;456(1):35-46. https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BJ20130418
In vivo activity: Dermal thickness of lesional skin sections was greater in BLM-treated mice than in phosphate-buffered saline (PBS)-treated mice on day 28 but was comparable on day 7. Of note, Am80 significantly attenuated BLM-induced dermal thickness on day 28 (Figure 1a). Consistent with this finding, Am80 treatment significantly reduced collagen content and mRNA expression of the Col1a1, Col1a2, Col3a1, and Col5a1 genes while promoting that of the Mmp13 gene in the lesional skin of BLM-treated mice (Figure 1b and c). Becasue transforming growth factor (TGF)-β1 and connective tissue growth factor (CTGF) are enough to induce experimental dermal fibrosis and their elevated expression is the hallmark of SSc dermal fibroblasts, the expression of these growth factors was examined. As expected, the decrease in mRNA expression of the Tgfb1 and Ctgf genes was noted in BLM-treated mice exposed to Am80 (Figure 1d), which was also confirmed at protein levels by immunohistochemistry (Figure 1e). To further elucidate the antifibrotic effect of Am80 on tissue fibrosis, TSK1 mice were employed, another widely accepted murine SSc model characterized by increased hypodermal thickness. In line with the results of BLM-treated mice, Am80 significantly ameliorated hypodermal thickness and collagen content in the back skin of TSK1 mice (Figure 1f and g). These findings suggest that Am80 exerts a potent antifibrotic effect on dermal fibrosis by reducing the production of collagen, promoting its degradation, and regulating expression of various soluble factors in SSc murine models. Reference: J Invest Dermatol. 2016 Feb;136(2):387-398. https://linkinghub.elsevier.com/retrieve/pii/S0022-202X(15)00059-7

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 17.6 50.00
Ethanol 17.6 50.00

Preparing Stock Solutions

The following data is based on the product molecular weight 351.44 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
In vitro protocol: 1. Lv XR, Zheng B, Li SY, Han AL, Wang C, Shi JH, Zhang XH, Liu Y, Li YH, Wen JK. Synthetic retinoid Am80 up-regulates apelin expression by promoting interaction of RARα with KLF5 and Sp1 in vascular smooth muscle cells. Biochem J. 2013 Nov 15;456(1):35-46. doi: 10.1042/BJ20130418. PMID: 23992409. 2. Jin Y, Wang L, Liu D, Lin X. Tamibarotene modulates the local immune response in experimental periodontitis. Int Immunopharmacol. 2014 Dec;23(2):537-45. doi: 10.1016/j.intimp.2014.10.003. Epub 2014 Oct 14. PMID: 25448496.
In vivo protocol: 1. Toyama T, Asano Y, Akamata K, Noda S, Taniguchi T, Takahashi T, Ichimura Y, Shudo K, Sato S, Kadono T. Tamibarotene Ameliorates Bleomycin-Induced Dermal Fibrosis by Modulating Phenotypes of Fibroblasts, Endothelial Cells, and Immune Cells. J Invest Dermatol. 2016 Feb;136(2):387-398. doi: 10.1016/j.jid.2015.10.058. Epub 2015 Nov 18. PMID: 26967475. 2. Kitaoka K, Shimizu N, Ono K, Chikahisa S, Nakagomi M, Shudo K, Ishimura K, Séi H, Yoshizaki K. The retinoic acid receptor agonist Am80 increases hippocampal ADAM10 in aged SAMP8 mice. Neuropharmacology. 2013 Sep;72:58-65. doi: 10.1016/j.neuropharm.2013.04.009. Epub 2013 Apr 23. PMID: 23624141.

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  1: Kitaoka K, Sano A, Chikahisa S, Yoshizaki K, Séi H. Disturbance of rapid eye movement sleep in senescence-accelerated mouse prone/8 mice is improved by retinoic acid receptor agonist Am80 (Tamibarotene). Neuroscience. 2010 May 19;167(3):573-82. Epub 2010 Feb 4. PubMed PMID: 20138974.

2: Sugitani M, Abe R, Ikarashi N, Ito K, Muratake H, Shudo K, Sugiyama K. Disposition of a new tamibarotene prodrug in mice. Biol Pharm Bull. 2009 Dec;32(12):1997-2001. PubMed PMID: 19952418.

3: Tacke R, Müller V, Büttner MW, Lippert WP, Bertermann R, Daiss JO, Khanwalkar H, Furst A, Gaudon C, Gronemeyer H. Synthesis and pharmacological characterization of Disila-AM80 (Disila-tamibarotene) and Disila-AM580, silicon analogues of the RARalpha-selective retinoid agonists AM80 (Tamibarotene) and AM580. ChemMedChem. 2009 Nov;4(11):1797-802. PubMed PMID: 19790202.

4: Kawahara K, Nishi K, Suenobu M, Ohtsuka H, Maeda A, Nagatomo K, Kuniyasu A, Staufenbiel M, Nakagomi M, Shudo K, Nakayama H. Oral administration of synthetic retinoid Am80 (Tamibarotene) decreases brain beta-amyloid peptides in APP23 mice. Biol Pharm Bull. 2009 Jul;32(7):1307-9. PubMed PMID: 19571405.

5: Fukui T, Kodera Y, Nishio K, Masuda N, Tamura T, Koizumi F. Synergistic interactions between the synthetic retinoid tamibarotene and glucocorticoids in human myeloma cells. Cancer Sci. 2009 Jun;100(6):1137-43. PubMed PMID: 19514122.

6: Nakazato T, Okudaira T, Ishikawa C, Nakama S, Sawada S, Tomita M, Uchihara JN, Taira N, Masuda M, Tanaka Y, Ohshiro K, Takasu N, Mori N. Anti-adult T-cell leukemia effects of a novel synthetic retinoid, Am80 (Tamibarotene). Cancer Sci. 2008 Nov;99(11):2286-94. Epub 2008 Sep 1. PubMed PMID: 18771528.

7: Miwako I, Kagechika H. Tamibarotene. Drugs Today (Barc). 2007 Aug;43(8):563-8. Review. PubMed PMID: 17925887.

8: Sanda T, Kuwano T, Nakao S, Iida S, Ishida T, Komatsu H, Shudo K, Kuwano M, Ono M, Ueda R. Antimyeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis. Leukemia. 2005 Jun;19(6):901-9. PubMed PMID: 15843826.

9: Tamibarotene: AM 80, retinobenzoic acid, Tamibaro. Drugs R D. 2004;5(6):359-62. Review. PubMed PMID: 15563242.

10: Shudo K, Kagechika H, Yamazaki N, Igarashi M, Tateda C. A synthetic retinoid Am80 (tamibarotene) rescues the memory deficit caused by scopolamine in a passive avoidance paradigm. Biol Pharm Bull. 2004 Nov;27(11):1887-9. Erratum in: Biol Pharm Bull. 2005 Dec;28(12):2346. PubMed PMID: 15516744.