Pan-retinoic acid receptor (RAR)
BMS493 targets all retinoic acid receptor subtypes (pan-RAR), including RARα, RARβ, and RARγ. As an inverse agonist, it stabilizes the receptor in an inactive conformation and increases the interaction of RARs with nuclear receptor corepressors such as NCoR. This action opposes the effects of retinoic acid and prevents retinoic acid-induced differentiation. The compound is a valuable tool for studying RAR signaling pathways.

BMS493 (100 nM; 6 days; ALDHhi UCB cells) treatment demonstrated a twofold increase in the number of ALDHhi cells accessible for transplantation compared to untreated controls. Newly introduced ALDHhi cells revealed higher numbers of CD34 and CD133 positive cells, as well as decreased expression of CD38, a marker produced by hematopoietic cells [1].

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In vitro, BMS493 inhibits retinoic acid-induced differentiation in various cell models. It has been shown to affect mouse bronchial tubule development, inhibit the activation of immature dendritic cells, and suppress leukemia blast cell differentiation. By acting as a pan-RAR inverse agonist, BMS493 modulates the transcriptional activity of RAR target genes and provides a tool for dissecting RAR-mediated cellular processes.

Intrapancreatic transplantation of cell progeny resulted in decreased hypertension in streptozotocin-treated NOD/SCID mice following the augmentation of ALDHhi cells with or without BMS493. Thus, during the ex vivo procedure, ALDHhi cells generated from umbilical cord blood (UCB) essentially lose their capacity to produce islets [1].

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In vivo, BMS493 has been used in developmental biology research to study the role of RAR signaling in various physiological processes. It affects mouse bronchial tubule development. The compound is also applied in cancer research to investigate the role of retinoid signaling in tumor biology. However, detailed in vivo efficacy data and specific animal study protocols are not extensively documented in the available literature.

Researchers have previously demonstrated that all-trans retinoic (atRA) induced growth inhibition and apoptosis in mouse embryonic palate mesenchymal cells (MEPM). In the present study, they investigated the molecular mechanisms of atRA-induced apoptosis and its putative action pathway. atRA-induced apoptosis is associated with activation of the initiator caspase-9 and the effector caspase-3, but not of the effector caspase-8. A broad caspase inhibitor (z-VAD-fmk), caspase-9 inhibitor z-LEHD-fmk and caspase-3 inhibitor (z-DEVD-fmk) blocked atRA-induced DNA fragmentation and sub-G1 fraction, but not caspase-8 inhibitor z-IETD-fmk. They further showed that atRA dose-dependently promoted mRNA expression of retinoic acid receptor beta (RAR-beta) and gamma. A weaker increase in RAR-alpha mRNA was seen only at the highest concentration of atRA (5 muM). The pan RAR antagonist, BMS493, completely abrogated atRA-induced DNA fragmentation, Sub-G1 fraction, and caspase-3 activation. Taken together, these findings show that caspase-mediated induction of apoptosis by atRA is an RAR-dependent signaling pathway.[2]

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Not specifically documented for BMS493. For RAR inverse agonists, cell-free binding assays typically measure the displacement of radiolabeled retinoic acid from RAR subtypes. The ability of BMS493 to enhance NCoR interaction with RARs can be assessed using biochemical assays such as co-immunoprecipitation or fluorescence resonance energy transfer (FRET)-based corepressor recruitment assays.

Cell Viability Assay[1]
Cell Types: ALDHhi UCB cells
Tested Concentrations: 100 nM
Incubation Duration: 6 days
Experimental Results: Shows a twofold increase in the number of ALDHhi cells available for transplantation compared to the untreated control group.

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In vitro cell-based assays for BMS493 include differentiation assays in various cell types. The compound has been used to study differentiation in airway cells, cancer cells, hematopoietic stem/progenitor cells, and monocytes. It prevents retinoic acid-induced differentiation and can be used to study the role of RAR signaling in cell fate decisions. Concentration ranges and treatment durations vary by cell type and experimental design.

In vivo studies with BMS493 have been conducted in animal models to investigate the role of RAR signaling in development and disease. The compound affects mouse bronchial tubule development. It is used in research areas including cancer, disease modeling, immunology, and stem cell biology. Specific dosing protocols and administration routes are not detailed in the available sources.

Pharmacokinetic data for BMS493 are not extensively documented. The compound is a small molecule with molecular weight 404.50 and formula C29H24O2. It is soluble in DMSO (35.14 mg/mL). Storage recommendations include -20°C for 3 years as powder or 4°C for 2 years. Detailed PK parameters have not been reported.

Specific toxicity data for BMS493 are not provided in the available literature. As a research compound, it is not intended for human therapeutic use. Standard laboratory safety precautions should be followed. The compound is supplied for research purposes only and is not for diagnostic or therapeutic use in humans or animals.

[1]. BMS 493 Modulates Retinoic Acid-Induced Differentiation During Expansion of Human Hematopoietic Progenitor Cells for Islet Regeneration. Stem Cells Dev. 2018 Aug 1;27(15):1062-1075.

[2]. Apoptosis induced by atRA in MEPM cells is mediated through activation of caspase and RAR. Toxicol Sci. 2006 Feb;89(2):504-9.

BMS-493 belongs to the dihydronaphthyl group of compounds, with the structure 1,2-dihydronaphthyl, substituted at positions 1, 1, 4, and 6 with methyl, phenylethynyl, and 2-(p-carboxyphenyl)vinyl groups, respectively (E-type isomers). It is a retinoic acid receptor antagonist. BMS-493 belongs to the benzoic acid, stilbene, dihydronaphthyl, and alkyne groups. Cell therapy is gradually becoming a new strategy for diabetes treatment. Therefore, in situ induction of endogenous islet regeneration is a feasible target for diabetes treatment. Previous studies have shown that umbilical cord blood-derived hematopoietic progenitor cells (HPCs) isolated with high aldehyde dehydrogenase activity (ALDH^hi) can reduce hyperglycemia after intrapancreatic transplantation (iPan) in streptozotocin (STZ)-treated non-obese diabetic (NOD)/severe combined immunodeficiency (SCID) mice. However, these cells are scarce and require in vitro expansion to reach the quantities needed for clinical application. Therefore, we investigated whether the inverse retinoic acid receptor agonist BMS 493 could inhibit retinoic acid-induced differentiation and maintain islet regeneration during expansion. Six days after expansion, the number of ALDH10 cells available for transplantation was doubled in BMS 493-treated cells compared to the untreated control group. Newly expanded ALDH10 cells showed an increased number of CD34 and CD133 positive cells and decreased expression of the hematopoietic differentiation marker CD38. Hematopoietic colony-forming capacity was similar between BMS 493-treated and untreated cells, with the expanded ALDH10 subset producing more colonies than the subset with low aldehyde dehydrogenase activity. To determine whether proteins secreted by these cells could enhance β-cell survival and/or proliferation in vitro, conditioned medium (CM) from BMS 493-treated or untreated cell expansions was added to human islet cultures. After culturing CM generated from cells treated with BMS 493 for 3 or 7 days, the total number of proliferating β cells increased. Compared with freshly isolated ALDHhi cells, progeny cells generated from HPC cells cultured with BMS 493 or without culture for 6 days failed to reduce hyperglycemia after iPan was transplanted into STZ-treated NOD/SCID mice. Therefore, further strategies are needed to reduce retinoic acid differentiation during HPC expansion in order to expand ALDHhi cells without losing pancreatic islet regeneration function. [1]

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BMS493 has the chemical formula C29H24O2 and a purity of ≥98%. It is also known as BMS 493 and is classified as a retinoid pathway modulator. The compound is used in research areas including cancer, developmental biology, immunology, and stem cell biology. It is applicable to human, mouse, rat, and non-human primate studies.

C29H24O2

404.51

404.178

C, 86.11; H, 5.98; O, 7.91

215030-90-3

9909190

White to light yellow solid powder

6.671

1

2

5

31

759

0

CC1(CC=C(C2=C1C=CC(=C2)/C=C/C3=CC=C(C=C3)C(=O)O)C#CC4=CC=CC=C4)C

YCADIXLLWMXYKW-CMDGGOBGSA-N

InChI=1S/C29H24O2/c1-29(2)19-18-24(14-10-21-6-4-3-5-7-21)26-20-23(13-17-27(26)29)9-8-22-11-15-25(16-12-22)28(30)31/h3-9,11-13,15-18,20H,19H2,1-2H3,(H,30,31)/b9-8+

4-[(E)-2-[5,5-dimethyl-8-(2-phenylethynyl)-6H-naphthalen-2-yl]ethenyl]benzoic acid

BMS-493; BMS 493; 4-{(E)-2-[5,5-dimethyl-8-(phenylethynyl)-5,6-dihydronaphthalen-2-yl]ethenyl}benzoic acid; 4-[(1E)-2-[5,6-Dihydro-5,5-dimethyl-8-(2-phenylethynyl)-2-naphthalenyl]ethenyl]benzoic acid; BMS-204493; CHEMBL472172; BMS-493

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 : ~50 mg/mL (~123.61 mM)

Solubility in Formulation 1: 2.08 mg/mL (5.14 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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: 2.08 mg/mL (5.14 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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: ≥ 2.08 mg/mL (5.14 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 20.8 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.)