A compound targeting ubiquitination to degrade Smad3
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A compound and ubiquitination technology, applied in the direction of peptides, etc., can solve problems that are not targets of anti-fibrosis therapy
Active Publication Date: 2018-05-08
THE FIRST AFFILIATED HOSPITAL OF SUN YAT SEN UNIV
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Problems solved by technology
Since SCF / Rocl acts on activated Smad3 after Smad3 is phosphorylated into the nucleus, it is not an ideal target for anti-fibrotic therapy
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Embodiment 1
[0034] Embodiment 1: The construction method of the compound targeting ubiquitination and degrading Smad3 of the present invention (the compound described here is called Protac)
[0035] 1. The method for constructing the compound Protac targeting ubiquitination and degrading Smad3 according to the present invention
[0036] ① Determination of Smad3 active site and preparation of Smad3 protein;
[0037] ② Enamine compound library preparation;
[0038] ③Glide step-by-step screening based on molecular docking;
[0039] ④ Hits results and analysis;
[0040] ⑤ Further screening of small molecules by Surface Plasmon Resonance (SPR) technology;
[0041] ⑥Construction and chemical synthesis of Protac;
[0042] ⑦Verification of Protac peptide structure.
[0043] 2. Construction results
[0044] (1) Determination and preparation of the active site of Smad3
[0045] The establishment of the active site of Smad3 is the prerequisite for molecular simulation. The ROC1-SCFFbw1a comp...
Embodiment 2
[0087] Example 2: Verification of the degradation of Smad3 by targeting the ubiquitination pathway of the compounds targeting ubiquitination and degradation of Smad3 according to the present invention
[0088] Cell culture: DMEM medium for human renal carcinoma cell line (ACHN) and rat normal renal fibroblast cell line (NRK-49F), human renal clear cell adenocarcinoma cell line (786-0) and human glomerular mesangium 1640 medium for cell line (HMC), both containing 10% calf serum, 50×10 3 U / L penicillin and 50mg / L streptomycin at 37°C, 5% CO 2 Under normal subculture conditions.
[0089] Western detection of VHL protein expression: Collect 786-0, ACHN, NRK-49F and HMC cells in a 100mm cell culture dish, rinse twice with PBS on ice, add 1ml RIPA cell lysate (Millipore, USA), and lyse on ice for 20min , centrifuge at 13000 rpm for 15 min, take 50 μl of supernatant, add 25 μl of 3×SDS loading buffer and boil for 8 min. Centrifuge at 13,000rpm for 15min, take 20 μl of the superna...
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Abstract
The present invention provides a compound targeting ubiquitination degradation of Smad3, wherein the compound targeting ubiquitination degradation Smad3 is a compound represented by formula (I) and ubiquitin ligase E3 represented by formula (II) The recognition ligand is formed by linking the two through the Linker shown in formula (III). The present invention combines computer simulation screening and targeted ubiquitination degradation protein technology to construct a compound that can specifically bind to Smad3 and target degradation of Smad3 protein through the ubiquitination pathway, and confirms that it can target ubiquitination degradation Smad3 protein. Since Smad3 is the most important signal protein known to cause fibrosis, this Protac has anti-fibrosis effect theoretically, and because of its small molecular weight, it can freely enter and exit cells, and it is likely to become a new drug for the treatment of fibrosis, which not only has scientific value It also has important social value.
Description
technical field [0001] The invention relates to a compound, in particular to a compound targeting ubiquitination to degrade Smad3. Background technique [0002] Organ fibrosis is the final outcome of many diseases in the human body, which leads to the failure of many organs including lungs, liver, kidneys, skin and so on. TGF-β is the most important known fibrosis factor, there are many downstream signaling pathways, and there are interactions and functional integration between different pathways, forming a very complex signal transduction network, in which the Smads pathway regulates TGF-β1 It plays a central role in the process of extracellular matrix (ECM) accumulation mediated. Numerous studies have shown that Smad3 is a key protein mediating TGF-β-induced fibrosis. Kidney fibrosis, inflammation, and apoptosis were significantly attenuated in the unilateral ureteral obstruction (UUO) model of Smad3 knockout mice (see Inazaki K, Kanamaru Y, Kojima Y, Sueyoshi N, Okumura...
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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06
Inventor 王欣
Owner THE FIRST AFFILIATED HOSPITAL OF SUN YAT SEN UNIV
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