Tamibarotene

Tamibarotene, Retinoic acid receptor α (RARα) agonist that induces differentiation (ED50 = 0.79 nM) and apoptosis of HL-60 cells in vitro. Tamibarotene exhibits antiproliferative effects against a variety of human tumor cells lines (mean values of 35, 40 and 60% growth inhibition at 0.1, 1 and 10 μM respectively) and displays anticancer activity against acute promyelocytic leukemia in vivo.

Refractory acute promyelocytic leukemia successfully treated with combination therapy of arsenic trioxide and tamibarotene: A case report.[Pubmed:27144119]

Leuk Res Rep. 2016 Jan 22;5:11-3.

A 40-year-old male developed refractory acute promyelocytic leukemia (APL) after various treatments including all-trans retinoic acid, Tamibarotene, arsenic trioxide (As2O3), conventional chemotherapy, and autologous peripheral blood stem cell transplantation. We attempted to use both Tamibarotene and As2O3 as a combination therapy, and he achieved molecular complete remission. Grade 2 prolongation of the QTc interval on the electrocardiogram was observed during the therapy. The combination therapy of As2O3 and Tamibarotene may be effective and tolerable for treating refractory APL cases who have no treatment options, even when they have previously been treated with Tamibarotene and As2O3 as a single agent.

Design, synthesis, and biological characterization of tamibarotene analogs as anticancer agents.[Pubmed:27113097]

Chem Biol Drug Des. 2016 Oct;88(4):542-55.

In our efforts of developing novel compounds as potential anticancer agents, a series of Tamibarotene analogs containing Zn(2+) -binding moieties were designed and developed. Biological characterization identified compound 7b as the most potent one with improved antiproliferative activities against multiple cancer cell lines, compared to parent compound Tamibarotene. Further characterization also demonstrated that compound 7b exhibited moderate activities as a histone deacetylase inhibitor with IC50 of 1.8 +/- 0.1 mum, thus suggesting that this could contribute to the improved antiproliferative activities of 7b. Pharmacokinetic studies revealed that compound 7b could release Tamibarotene after administration and prolong the circulation time of Tamibarotene, and this may also potentially contribute to the improved antiproliferative activities. Collectively, the results demonstrated that compound 7b could serve as a new lead for further development of more potent analogs as potential anticancer agents.

Tamibarotene Ameliorates Bleomycin-Induced Dermal Fibrosis by Modulating Phenotypes of Fibroblasts, Endothelial Cells, and Immune Cells.[Pubmed:26967475]

J Invest Dermatol. 2016 Feb;136(2):387-398.

Tamibarotene (Am80) is a synthetic retinoid that modulates the pathologic processes of various autoimmune and inflammatory diseases and their animal models. We here investigated the therapeutic potential of Am80 against systemic sclerosis using its animal models. Am80 significantly attenuated dermal and hypodermal fibrosis in bleomycin (BLM)-treated mice and tight skin 1 mice, respectively. Consistently, Am80 significantly suppressed the expression of various molecules related to tissue fibrosis, including transforming growth factor-beta1, connective tissue growth factor, IL-4, IL-10, IL-13, IL-17A, tumor necrosis factor-alpha, IFN-gamma, and monocyte chemotactic protein 1 in the lesional skin of BLM-treated mice. Furthermore, Am80 decreased the proportion of effector T cells, while increasing that of naive T cells among CD4+ T cells in the draining lymph nodes of BLM-treated mice. Moreover, a series of BLM-induced pathologic events, including endothelial-to-mesenchymal transition; ICAM-1 expression in endothelial cells; the infiltration of macrophages, mast cells, and lymphocytes; and M2 macrophage differentiation, were attenuated by Am80. Importantly, Am80 directly reversed the profibrotic phenotype of transforming growth factor-beta1-treated dermal fibroblasts, suppressed ICAM-1 expression in endothelial cells, and promoted M1 macrophage differentiation in vitro. Collectively, Am80 inhibits the development of experimental dermal fibrosis by reversing the profibrotic phenotype of various cell types and would be a candidate for therapeutic drugs against dermal fibrosis of systemic sclerosis.

An Open-labeled, Multicenter Phase II Study of Tamibarotene in Patients with Steroid-refractory Chronic Graft-versus-Host Disease.[Pubmed:27777437]

Acta Med Okayama. 2016 Oct;70(5):409-412.

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation (HSCT). Retinoic acid (Tamibarotene) exerts multiple effects on cell differentiation and is clinically used for the treatment of acute promyelocytic leukemia. Tamibarotene down-regulates both Th1 and Th17 differentiation in donor T cells after allogeneic HSCT, resulting in attenuation of experimental chronic GVHD. Based on preclinical data, we have launched a phase II study of Tamibarotene in patients with steroid-refractory chronic GVHD. This study will clarify whether Tamibarotene can exert beneficial effects in patients with steroid-refractory chronic GVHD.

The effect of Am-80, a synthetic retinoid, on spinal cord injury-induced motor dysfunction in rats.[Pubmed:19182380]

Biol Pharm Bull. 2009 Feb;32(2):225-31.

The present study investigated the effect of 4[(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthalenyl)carbamoyl] benzoic acid (Am-80), a synthetic retinoid, on spinal cord injury (SCI) in rats. Treatment with Am-80 (orally and subcutaneously) significantly promoted recovery from SCI-induced motor dysfunction. On day 28 after injury, the lesion cavity was markedly reduced, while the expression of myelin basic protein (MBP; myelin), betaIIItubulin (neuron), and glial fibrillary acidic protein (GFAP; astrocyte) was increased, in comparison with SCI controls. Interestingly, expression of neurotrophin receptor, tyrosine kinase B (TrkB) was over 3-fold higher after Am-80 treatment than in SCI controls. A lot of TrkB-positive cells as well as brain-derived neurotrophic factor (BDNF)-positive ones were observed around the injured site. Am-80 (10 microM) combined with BDNF (100 ng/ml) promoted extensive neurite outgrowth and TrkB gene expression by cultured SH-SY5Y cells, as did all-trans retinoic acid (ATRA). Thymidine incorporation was dramatically suppressed, but there was little effect on cell viability. These findings suggest that Am-80 has the potential to be used for treating neurodegenerative disorders, including SCI. Its efficacy may be partly ascribed to promotion of cell viability and differentiation of neural stem cells through increased TrkB expression.

RARalpha is a regulatory factor for Am-80-induced cell growth inhibition of hematologic malignant cells.[Pubmed:17611697]

Int J Oncol. 2007 Aug;31(2):397-404.

Retinoids are used for treatment of acute promyelocytic leukemia (APL). Am-80, Tamibarotene, binds to retinoic acid receptor alpha (RARalpha) more specifically than all-trans retinoic acid. We studied the tumor cell suppressive effects of Am-80, with respect to cytotoxicity and growth inhibition using eight myeloid and lymphoid malignant cells in culture (HL-60, HL-60R, K-562, Kasumi-1, MEG01, Raji, U266B1, and U937). The effects of Am-80 were examined during 9 days of incubation with 10(-7)-10(-5) M of Am-80 in culture medium, which was changed every 3 days. HL-60 were the only cells sensitive to Am-80-induced cytotoxicity; the latter reached more than 95% after 9 days of incubation, and death was primarily through apoptosis. The total mass of RARalpha in HL-60 was significantly greater (p<0.006) than in ATRA-resistant HL-60 (HL-60R) as well as all of other cells tested. However, in all cells excluding HL-60, Am-80 induced time- and dose-dependent cell growth inhibition without noticeable cytotoxicity. TGF-beta2 was released into the media containing cells incubated with Am-80 for 3 days. A dose-dependent increment of phosphorylation of Smad-2 was also detected. The relative amount of secreted TGF-beta2 correlated with the growth inhibition rates in all cells tested excluding HL-60, and with the total mass of RARalpha in the cells (p=0.0137). Our results indicate that Am-80-induced cell-type non-specific growth inhibition is mediated by TGF-beta2, where the total mass of RARalpha could be an important regulatory factor in hematologic malignant cells.

Retinobenzoic acids. 1. Structure-activity relationships of aromatic amides with retinoidal activity.[Pubmed:3184125]

J Med Chem. 1988 Nov;31(11):2182-92.

Two types of aromatic amides, terephthalic monoanilides and (arylcarboxamido)benzoic acids, have been shown to possess potent retinoidal activities and can be classified as retinoids. The structure-activity relationships of these amides are discussed on the basis of differentiation-inducing activity on human promyelocytic leukemia cells HL-60. In generic formula 4 (X = NHCO or CONH), the necessary factors to elicit the retinoidal activities are a medium-sized alkyl group (isopropyl, tert-butyl, etc.) at the meta position and a carboxyl group at the para position of the other benzene ring. The bonding of the amide structure can be reversed, this moiety apparently having the role of locating the two benzene rings at suitable positions with respect to each other. Substitution at the ring position ortho to the amide group or N-methylation of the amide group caused loss of activity, presumably owing to the resultant change of conformation. It is clear that the mutual orientation of the benzylic methyl group(s) and the carboxyl group and their distance apart are essential factors determining the retinoidal activity. Among the synthesized compounds, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benz oic acid (Am80) and 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido] benzoic acid (Am580) were several times more active than retinoic acid in the assay. They are structurally related to retinoic acid, as is clear from the biological activity of the hybrid compounds (M2 and R2).