SR-318
目录号 : GC39574A dual inhibitor of p38α and p38β MAPKs
Cas No.:2413286-32-3
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
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- Purity: >98.50%
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- Datasheet
SR 318 is a dual inhibitor of p38α and p38β MAPKs (IC50s = 5 and 32 nM, respectively).1 It is selective for p38α and p38β MAPKs over a panel of 468 kinases at 1 ?M. SR 318 inhibits LPS-induced TNF-α release in isolated human whole blood (IC50 = 0.283 ?M).
1.R?hm, S., Berger, B.-T., Schr?der, M., et al.Fast iterative synthetic approach toward identification of novel highly selective p38 MAP kinase inhibitorsJ. Med. Chem.62(23)10757-10782(2019)
Cas No. | 2413286-32-3 | SDF | |
Canonical SMILES | O=C(C1=C(N)N(C2=CC=CC=C2)N=C1)NCC3=CC=C(C(NCCCC4CCCCC4)=O)C=C3 | ||
分子式 | C27H33N5O2 | 分子量 | 459.58 |
溶解度 | DMSO: 125 mg/mL (271.99 mM) | 储存条件 | 4°C, protect from light |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.1759 mL | 10.8795 mL | 21.759 mL |
5 mM | 0.4352 mL | 2.1759 mL | 4.3518 mL |
10 mM | 0.2176 mL | 1.0879 mL | 2.1759 mL |
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2.
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Selective targeting of the αC and DFG-out pocket in p38 MAPK
Eur J Med Chem 2020 Dec 15;208:112721.PMID:33035818DOI:10.1016/j.ejmech.2020.112721.
The p38 MAPK cascade is a key signaling pathway linked to a multitude of physiological functions and of central importance in inflammatory and autoimmune diseases. Although studied extensively, little is known about how conformation-specific inhibitors alter signaling outcomes. Here, we have explored the highly dynamic back pocket of p38 MAPK with allosteric urea fragments. However, screening against known off-targets showed that these fragments maintained the selectivity issues of their parent compound BIRB-796, while combination with the hinge-binding motif of VPC-00628 greatly enhanced inhibitor selectivity. Further efforts focused therefore on the exploration of the αC-out pocket of p38 MAPK, yielding compound 137 as a highly selective type-II inhibitor. Even though 137 is structurally related to a recent p38 type-II chemical probe, SR-318, the data presented here provide valuable insights into back-pocket interactions that are not addressed in SR-318 and it provides an alternative chemical tool with good cellular activity targeting also the p38 back pocket.
Fast Iterative Synthetic Approach toward Identification of Novel Highly Selective p38 MAP Kinase Inhibitors
J Med Chem 2019 Dec 12;62(23):10757-10782.PMID:31702918DOI:10.1021/acs.jmedchem.9b01227.
p38 mitogen-activated protein kinases are key mediators of environmental stress response and are promising targets for treatment of inflammatory diseases and cancer. Numerous efforts have led to the discovery of several potent inhibitors; however, so far no highly selective type-II inhibitors have been reported. We previously identified VPC-00628 as a potent and selective type-II inhibitor of p38α/β with few off-targets. Here we analyzed the chemical building blocks of VPC-00628 that played a key role in achieving potency and selectivity through targeting an inactive state of the kinases induced by a unique folded P-loop conformation. Using a rapid, systematic combinatorial synthetic approach, we identified compound 93 (SR-318) with excellent potency and selectivity for p38α/β, which potently inhibited the TNF-α release in whole blood. SR-318 therefore presents a potent and selective type-II inhibitor of p38α/β that can be used as a chemical probe for targeting this particular inactive state of these two p38 isoforms.