T-5224
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MedKoo CAT#: 206216

CAS#: 530141-72-1

Description: T-5224 is a selective inhibitor of c-Fos/activator protein-1. T-5224 ameliorates liver injury and improves survival through decreasing production of proinflammatory cytokines and chemokines in endotoxemic mice. T-5224 has been investigated in phase II human clinical trials. T-5224 may be a promising new treatment for septic kidney injury. Activator protein 1 (AP-1) is a pivotal transcription factor that regulates a wide range of cellular processes including proliferation, apoptosis, differentiation, survival, cell migration, and transformation.


Chemical Structure

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T-5224
CAS# 530141-72-1

Theoretical Analysis

MedKoo Cat#: 206216
Name: T-5224
CAS#: 530141-72-1
Chemical Formula: C29H27NO8
Exact Mass: 517.17367
Molecular Weight: 517.52658
Elemental Analysis: C, 67.30; H, 5.26; N, 2.71; O, 24.73

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10.0mg USD 150.0 Same day
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100.0mg USD 750.0 Same day
200.0mg USD 1250.0 Same day
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1.0g USD 3450.0 Same day
2.0g USD 5850.0 Same day
5.0g USD 9850.0 2 Weeks
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Synonym: T5224, T-5224, T 5224

IUPAC/Chemical Name: 3-(5-(4-(cyclopentyloxy)-2-hydroxybenzoyl)-2-((3-hydroxybenzo[d]isoxazol-6-yl)methoxy)phenyl)propanoic acid

InChi Key: DALCQQSLNPLQFZ-UHFFFAOYSA-N

InChi Code: InChI=1S/C29H27NO8/c31-24-15-21(37-20-3-1-2-4-20)8-10-22(24)28(34)19-6-11-25(18(14-19)7-12-27(32)33)36-16-17-5-9-23-26(13-17)38-30-29(23)35/h5-6,8-11,13-15,20,31H,1-4,7,12,16H2,(H,30,35)(H,32,33)

SMILES Code: O=C(O)CCC1=CC(C(C2=CC=C(OC3CCCC3)C=C2O)=O)=CC=C1OCC4=CC5=C(C=C4)C(O)=NO5

Appearance: White to off-white crystalline solid

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

Biological target: T-5224 is a transcription factor c-Fos/activator protein (AP)-1 inhibitor.
In vitro activity: T-5224, was newly generated from a cyclic disulfide decapeptide designed by 3D pharmacophore modeling based on the X-ray crystal structure of the basic region–leucine zipper domain of the AP-1–DNA complex. IL-1β treatment of human NP cells significantly increased the expression of c-Fos mRNA in human NP cells, and the levels of c-Fos in the nucleus increased with time (Fig. 1a–c). Further, the levels of MMP-3, MMP-13, ADAMTS-5 and IL-1β mRNAs were significantly increased by IL-1β treatment and significantly decreased by T-5224 in a dose-dependent manner (Fig. 1d). Inhibition of the IL-1β induced up-regulation of MMP-3 and -13 by T-5224 was apparent in immunofluorescence staining (Fig. 1e). Reference: Sci Rep. 2017; 7: 16983. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717052/
In vivo activity: HMGB-1 is a late mediator of lethal systemic inflammation in animal models of cytokine-mediated sepsis. Activated macrophages release HMGB-1 after a lag of 12–18 h. Serum HMGB-1 concentration 18 h after LPS injection was significantly higher than that of controls (Table 1), and oral administration of T-5224 immediately after LPS injection inhibited serum HMGB-1 increases. Survival rates at 72 h post-LPS injection were 40 % (Fig. 1). However, in mice treated with T-5224, survival rates at the corresponding time point after LPS injection increased to 80 % (Fig. 1, P < 0.01). Reference: J Intensive Care. 2015; 3: 49. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647501/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 30.5 58.93
DMSO:PBS (pH 7.2) (1:2) 0.33 0.64
DMF 30.0 57.97

Preparing Stock Solutions

The following data is based on the product molecular weight 517.52658 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: 1. Makino H, Seki S, Yahara Y, Shiozawa S, Aikawa Y, Motomura H, Nogami M, Watanabe K, Sainoh T, Ito H, Tsumaki N, Kawaguchi Y, Yamazaki M, Kimura T. A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebral disc degeneration and associated pain. Sci Rep. 2017 Dec 5;7(1):16983. doi: 10.1038/s41598-017-17289-y. PMID: 29208967; PMCID: PMC5717052. 2. Avouac J, Palumbo K, Tomcik M, Zerr P, Dees C, Horn A, Maurer B, Akhmetshina A, Beyer C, Sadowski A, Schneider H, Shiozawa S, Distler O, Schett G, Allanore Y, Distler JH. Inhibition of activator protein 1 signaling abrogates transforming growth factor β-mediated activation of fibroblasts and prevents experimental fibrosis. Arthritis Rheum. 2012 May;64(5):1642-52. doi: 10.1002/art.33501. PMID: 22139817. 3. Kamide D, Yamashita T, Araki K, Tomifuji M, Tanaka Y, Tanaka S, Shiozawa S, Shiotani A. Selective activator protein-1 inhibitor T-5224 prevents lymph node metastasis in an oral cancer model. Cancer Sci. 2016 May;107(5):666-73. doi: 10.1111/cas.12914. Epub 2016 Apr 26. PMID: 26918517; PMCID: PMC4970834. 4. Ishida M, Ueki M, Morishita J, Ueno M, Shiozawa S, Maekawa N. T-5224, a selective inhibitor of c-Fos/activator protein-1, improves survival by inhibiting serum high mobility group box-1 in lethal lipopolysaccharide-induced acute kidney injury model. J Intensive Care. 2015 Nov 14;3:49. doi: 10.1186/s40560-015-0115-2. PMID: 26579229; PMCID: PMC4647501.
In vitro protocol: 1. Makino H, Seki S, Yahara Y, Shiozawa S, Aikawa Y, Motomura H, Nogami M, Watanabe K, Sainoh T, Ito H, Tsumaki N, Kawaguchi Y, Yamazaki M, Kimura T. A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebral disc degeneration and associated pain. Sci Rep. 2017 Dec 5;7(1):16983. doi: 10.1038/s41598-017-17289-y. PMID: 29208967; PMCID: PMC5717052. 2. Avouac J, Palumbo K, Tomcik M, Zerr P, Dees C, Horn A, Maurer B, Akhmetshina A, Beyer C, Sadowski A, Schneider H, Shiozawa S, Distler O, Schett G, Allanore Y, Distler JH. Inhibition of activator protein 1 signaling abrogates transforming growth factor β-mediated activation of fibroblasts and prevents experimental fibrosis. Arthritis Rheum. 2012 May;64(5):1642-52. doi: 10.1002/art.33501. PMID: 22139817.
In vivo protocol: 1. Kamide D, Yamashita T, Araki K, Tomifuji M, Tanaka Y, Tanaka S, Shiozawa S, Shiotani A. Selective activator protein-1 inhibitor T-5224 prevents lymph node metastasis in an oral cancer model. Cancer Sci. 2016 May;107(5):666-73. doi: 10.1111/cas.12914. Epub 2016 Apr 26. PMID: 26918517; PMCID: PMC4970834. 2. Ishida M, Ueki M, Morishita J, Ueno M, Shiozawa S, Maekawa N. T-5224, a selective inhibitor of c-Fos/activator protein-1, improves survival by inhibiting serum high mobility group box-1 in lethal lipopolysaccharide-induced acute kidney injury model. J Intensive Care. 2015 Nov 14;3:49. doi: 10.1186/s40560-015-0115-2. PMID: 26579229; PMCID: PMC4647501.

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1: Ye N, Ding Y, Wild C, Shen Q, Zhou J. Small Molecule Inhibitors Targeting Activator Protein 1 (AP-1). J Med Chem. 2014 Aug 28;57(16):6930-48. doi: 10.1021/jm5004733. Epub 2014 May 27. PubMed PMID: 24831826; PubMed Central PMCID: PMC4148154.

2: Miyazaki H, Morishita J, Ueki M, Nishina K, Shiozawa S, Maekawa N. The effects of a selective inhibitor of c-Fos/activator protein-1 on endotoxin-induced acute kidney injury in mice. BMC Nephrol. 2012 Nov 23;13:153. doi: 10.1186/1471-2369-13-153. PubMed PMID: 23173923; PubMed Central PMCID: PMC3557146.

3: Izuta S, Ueki M, Ueno M, Nishina K, Shiozawa S, Maekawa N. T-5224, a selective inhibitor of c-Fos/activator protein-1, attenuates lipopolysaccharide-induced liver injury in mice. Biotechnol Lett. 2012 Dec;34(12):2175-82. doi: 10.1007/s10529-012-1022-4. Epub 2012 Aug 25. PubMed PMID: 22927112.

4: Avouac J, Palumbo K, Tomcik M, Zerr P, Dees C, Horn A, Maurer B, Akhmetshina A, Beyer C, Sadowski A, Schneider H, Shiozawa S, Distler O, Schett G, Allanore Y, Distler JH. Inhibition of activator protein 1 signaling abrogates transforming growth factor β-mediated activation of fibroblasts and prevents experimental fibrosis. Arthritis Rheum. 2012 May;64(5):1642-52. doi: 10.1002/art.33501. PubMed PMID: 22139817.

5: Uchihashi S, Fukumoto H, Onoda M, Hayakawa H, Ikushiro S, Sakaki T. Metabolism of the c-Fos/activator protein-1 inhibitor T-5224 by multiple human UDP-glucuronosyltransferase isoforms. Drug Metab Dispos. 2011 May;39(5):803-13. doi: 10.1124/dmd.110.037952. Epub 2011 Feb 23. PubMed PMID: 21346002.

T-5224

10.0mg / USD 150.0