T-5224
T-5224 is a non-peptidic, small molecule and novel inhibitor of c-Fos/AP-1 [1].
T-5224 has shown the specific inhibition in a c-Fos/AP-1promoter-luciferase assay, without affecting the levels of c-Fos family protein members themselves. In addition, T-5224 has been reported to selectively inhibit the DNA binding activity of c-Fos/c-Jun, without affecting those of other transcription factors(C/EBPα and ATF-2, MyoD, Sp-1 and NF-κB/p65). Some research has been suggested that T-5224 potently suppressed the development of collagen-induced arthritis (CIA). Besides, T-5224 has been evidenced to inhibit the expression of nuclear factor of activated T-cells (NFAT) and osteoclastogenesis of the macrophage-osteoclast precursor RAW264.7cells induced by receptor activator of NF-κB ligand (RANKL). Apart from these, T-5224 has been noted to inhibit in-vitro production of the mediators (MMP-1, MMP-3, IL-6 and TNF-α) in IL-1β-stimulated human synovial SW982 cells with the mean IC50 of about 10μM. In the in vivo pharmacokinetic analysis, the ED50 of T-5224 is about 1-10mg/kg, and the Cmax is 0.03-0.5μM [1].
References:
[1] Aikawa Y1, Morimoto K, Yamamoto T, Chaki H, Hashiramoto A, Narita H, Hirono S, Shiozawa S. Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1. Nat Biotechnol. 2008 Jul;26(7):817-23.
- 1. Jie Wang, Chunlin Wang, et al. "FLI1 induces erythroleukemia through opposing effects on UBASH3A and UBASH3B expression." BMC Cancer. 2024 Mar 9;24(1):326. PMID: 38461240
- 2. Seung Hyun Han, et al. "Bacillus subtilis Induces Human Beta Defensin-2 Through its Lipoproteins in Human Intestinal Epithelial Cells." Probiotics Antimicrob Proteins. 2024 Feb 20. PMID: 38376819
- 3. Viviana Cobos Jiménez, Aviva Geretz, et al. "AP-1/c-Fos supports SIV and HIV-1 latency in CD4 T cells infected in vivo." iScience. 2023 Sep 22;26(10):108015. PMID: 37860759
- 4. Susumu Ohya, Miki Matsui, et al. "Downregulation of IL-8 and IL-10 by the Activation of Ca2+-Activated K+ Channel KCa3.1 in THP-1-Derived M2 Macrophages." Int J Mol Sci. 2022 Aug 3;23(15):8603. PMID: 35955737
- 5. Qian Zhao, Kaixin Zhang, et al. "OLFML2A is necessary for anti-triple negative breast cancer effect of selective activator protein-1 inhibitor T-5224." Transl Oncol. 2021 Aug;14(8):101100. PMID: 33993098
- 6. Rengyun Liu, Jie Tan, et al. "Therapeutic targeting of FOS in mutant TERT cancers through removing TERT suppression of apoptosis via regulating survivin and TRAIL-R2." Proc Natl Acad Sci U S A. 2021 Mar 16;118(11):e2022779118. PMID: 33836600
- 7. Philipp Novoszel, Martin Holcmann, et al. "Psoriatic skin inflammation is promoted by c-Jun/AP-1-dependent CCL2 and IL-23 expression in dendritic cells." EMBO Mol Med. 2021 Apr 9;13(4):e12409. PMID: 33724710
- 8. Xinh-Xinh Nguyen, Tetsuya Nishimoto, et al. "Lysyl oxidase directly contributes to extracellular matrix production and fibrosis in systemic sclerosis." Am J Physiol Lung Cell Mol Physiol. 2021 Jan 1;320(1):L29-L40. PMID: 33026236
- 9. Drummond RA, Swamydas M, et al. "CARD9(+) microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment." Nat Immunol. 2019 May;20(5):559-570. PMID: 30996332
- 10. Lv SY, Cui B, et al. "Spexin/NPQ Induces Fos and Produces Antinociceptive Effect against Inflammatory Pain in the Mouse Model." Am J Pathol. 2019 Jan 19. pii:S0002-9440(18)30290-6. PMID: 30664863
- 11. Choi Y, Rosewell KL, et al. "FOS, a Critical Downstream Mediator of PGR and EGF-signaling Necessary for Ovulatory Prostaglandins in the Human Ovary." J Clin Endocrinol Metab. 2018 Aug 16. PMID: 30124866
- 12. Levi NJ, Wilson CW, et al. "Obesity-related cellular stressors regulate gonadotropin releasing hormone gene expression via c-Fos/AP-1." Mol Cell Endocrinol. 2018 Jul 29. pii: S0303-7207(18)30235-1. PMID: 30063946
- 13. Chih-Wei Chen. "WNT5A induziert über eine JNK-abhängige Aktivierung von latentem TGF-β Fibrose." Friedrich-Alexander-Universität Erlangen-ürnberg.2018/01/15.
- 14. Isha Dey, Neil A. Bradbury. "Activation of TPA-response element present in human Lemur Tyrosine Kinase 2 (lmtk2) gene increases its expression." Biochemistry and Biophysics Reports. 2017 September 21.
- 15. Shao YY, Hsieh MS, et al. "Hepatitis C virus core protein potentiates proangiogenic activity of hepatocellular carcinoma cells." Oncotarget. 2017 Sep 30;8(49):86681-86692. PMID: 29156827
- 16. Jang B, Ishigami A, et al. "The Peptidylarginine Deiminase Inhibitor Cl-Amidine Suppresses Inducible Nitric Oxide Synthase Expression in Dendritic Cells." Int J Mol Sci. 2017 Oct 27;18(11). pii: E2258. PMID: 29077055
- 17. Johannessen L, Sundberg TB, et al. "Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells. "Nat Chem Biol. 2017 Oct;13(10):1102-1108. PMID: 28805801
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| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 517.53 |
| Cas No. | 530141-72-1 |
| Formula | C29H27NO8 |
| Solubility | ≥25.88 mg/mL in DMSO; insoluble in H2O; insoluble in EtOH |
| Chemical Name | 3-(5-(4-(cyclopentyloxy)-2-hydroxybenzoyl)-2-((3-oxo-2,3-dihydrobenzo[d]isoxazol-6-yl)methoxy)phenyl)propanoic acid |
| SDF | Download SDF |
| Canonical SMILES | O=C1NOC2=CC(COC(C=CC(C(C3=C(O)C=C(OC4CCCC4)C=C3)=O)=C5)=C5CCC(O)=O)=CC=C12 |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Kinase experiment [1]: | |
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Inhibitory activities |
The DNA binding activity of transcription factors was measured using the TransAM kits (Active Motif). Nuclear extracts containing factors such as c-Fos/AP-1, c-Jun/AP-1, ATF-2, C/EBPa, MyoD, Sp-1 or NF-kB/p65 and various concentrations of T-5224 were added in the multi-well plates precoated with respective consensus double-stranded (ds)DNA oligomers. After incubation for 1 h, the transcription factor bound to its respective consensus dsDNA sequences was detected by using antibodies reactive against the respective transcription factors according to the manufacturer’s protocol. |
| Cell experiment [2]: | |
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Cell lines |
Human synovial SW982 cells; human chondrocyte SW1353 cells |
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Preparation method |
Dissolved in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
0.1, 1, 10, 100, 1000 μM. |
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Applications |
In human synovial SW982 cells stimulated by IL-1β, T-5224 inhibits the production of MMP-1, MMP-3, IL-6 and TNFα. In human chondrocyte SW1353 cells stimulated by IL-1β, T-5224 inhibits the production of MMP-3 and MMP-13 with IC50 value of 10 μM. |
| Animal experiment [3]: | |
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Animal models |
Male DBA/1J mice with type II collagen–induced arthritis (CIA). |
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Dosage form |
0.3, 1, 3, 30 mg/kg, once daily from day 21, before the onset of arthritis; administered orally. |
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Applications |
T-5224 significantly inhibits the development of arthritis by 64% and 91% on day 50 at 3 and 30 mg/kg, respectively. T-5224 inhibits joint destruction and completely protects the joint from destruction at 30 mg/kg. At 30 mg/kg dose, T-5224 significantly inhibits MMP-2, MMP-3, MMP-9, MMP-13, IL-1β, IL-6 and TNFα. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Aikawa Y, Morimoto K, Yamamoto T, et al. Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1. Nat Biotechnol, 2008, 26(7): 817-823. |
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