| 名稱 | T-5224 |
| 描述 | T-5224 is a transcription factor c-Fos/AP-1 inhibitor, which specifically inhibits the DNA binding activity of c-Fos/c-Jun without affecting other transcription factors. |
| 細胞實驗 | NIH/3T3 cells were transiently transfected with the luciferase reporter plasmids pAP-1-Luc (× 7 TGACTAA), pNF-kB-Luc (× 5 TGGGGACTTTCCGC) or control phRL-TK, and cultured overnight. Cells were incubated in 0.5% FBS/DMEM containing T-5224 for 1 h, and then stimulated with PMA (10 ng/ml) or TNFa (10 ng/ml), and then cultured for 3 h, followed by measurement of lysate by using dual-luciferase reporter assay system [1]. |
| 激酶實驗 | The DNA binding activity of transcription factors was measured using the TransAM kits. 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 [1]. |
| 動物實驗 | Mice were housed in an SPF (specific pathogen-free) grade environment and provided food and water ad libitum with a 12 h:12 h light/dark cycle. Male 8-week-old DBA/1J mice were immunized with bovine type II collagen emulsified in Freund's complete adjuvant on days 0 and 21. T-5224, MTX and LEF were orally administered once per day. Arthritis was assessed in a blind fashion for four paws per mouse using the following score: 0, uninvolved; 1, swelling of ≤2 toes or slight swelling in ankles and wrists; 2, swelling of ≥3 toes or moderate swelling in ankles and wrists; 3, extensive swelling of total paw. X-ray films of four paws taken using Softex were assessed for joint destruction in 2nd to 5th proximal interphalangeal joints and five metatarsophalangeal joints of four paws, the carpal joints of the forepaws, and the tarsal and calcaneal joints of the hind paws. Score was: 0, no change; 1, partial erosion; 2, complete erosion for joints; and 0, negative; 0.5, positive for osteoporosis. IL-1β (500 ng per unilateral hind paw) was administered into the footpads. The mice with ≥1 arthritis score were treated with either anti-TNFα antibody at 50 or 250 μg/mouse, intraperitoneally (i.p.) twice a week and/or with 3 mg/kg T-5224, orally once daily [1]. |
| 體外活性 | IL-1b刺激下的人類滑膜SW982細胞產(chǎn)生滑膜細胞介質(zhì)MMP-1、MMP-3、IL-6和TNFα的體外生產(chǎn)，以及IL-1b刺激下的人類軟骨細胞SW1353細胞產(chǎn)生軟骨炎癥介質(zhì)MMP-3和MMP-13，均被T-5224所抑制。大多數(shù)細胞實驗的IC50值約為10μM [1]。加壓素選擇性地刺激CDS1 mRNA的增加，這一過程依賴于蛋白激酶C，并可被AP-1抑制劑T-5224所抑制 [3]。T-5224顯著以劑量依賴的方式抑制HNSCC細胞的侵襲、遷移和MMP活性；而對細胞增殖沒有顯著影響 [4]。 |
| 體內(nèi)活性 | T-5224通過每日一次從第21天開始使用，有效抑制了膠原蛋白誘導(dǎo)的關(guān)節(jié)炎(CIA)的發(fā)展，在第50天時，3 mg/kg和30 mg/kg劑量的T-5224分別抑制了關(guān)節(jié)炎的發(fā)展64%和91%。接受T-5224治療的小鼠體重穩(wěn)定恢復(fù)。X光研究顯示，接受治療的關(guān)節(jié)破壞得到了抑制，未經(jīng)治療的關(guān)節(jié)炎對照組則沒有這種現(xiàn)象，特別是，30 mg/kg的T-5224完全保護了關(guān)節(jié)不受破壞[1]。在腹腔注射LPS后，口服給予T-5224 (300 mg/kg)能顯著保護，對抗急性血清TNFα、HMGB1、ALT/AST水平的升高以及肝組織中MIP-1α和MCP-1的水平，減少了致死率(27%)[2]。T-5224 (150 mg/kg)或安慰劑每日口服4周。在模型中，接受T-5224治療組的頸淋巴結(jié)轉(zhuǎn)移率為40.0%，而安慰劑治療組為74.1%[4]。 |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | 10% DMSO+40% PEG300+5% Tween 80+45% Saline : 5 mg/mL (9.66 mM), Suspension. Please add co-solvents sequentially, clarifying the solution as much as possible before adding the next one. Dissolve by heating and/or sonication if necessary. Working solution is recommended to be prepared and used immediately.
H2O : Insoluble
DMSO : 16.67 mg/mL (32.2 mM)
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| 關(guān)鍵字 | Activator Protein 1 | Inhibitor | inhibit | T-5224 | Matrix metalloproteinases | MMP | T 5224 | AP-1 | T5224 |
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