SHP2 allosteric inhibitor TK-453 alleviates psoriasis-like skin inflammation in mice via inhibition of IL-23/Th17 axis.
SHP2 allosteric inhibitor TK-453 alleviates psoriasis-like skin inflammation in mice via inhibition of IL-23/Th17 axis.
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SHP2 变构抑制剂 TK-453 通过抑制 IL-23/Th17 轴减轻小鼠银屑病样皮肤炎症
DOI：
10.1016/j.isci.2022.104009
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发表时间：
2022-04-15
期刊：
影响因子：
5.8
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Wang M;Li T;Ouyang Z;Tang K;Zhu Y;Song C;Sun H;Yu B;Ji X;Sun Y
SHP2是由PTPN11编码的第一个致癌酪氨酸磷酸酶，它在癌症和炎症相关疾病中起着重要的调节作用，尽管SHP2抑制剂已在II/II期临床试验中用于实体抑制作用，无论SHP2抑制了Protigity and protient and Persecte and persection and percortife and persected and persected and persection shep2对于不同的构象SHP2。吡嗪环平面相对于SHP099的iatiation。此外，TK-453通过抑制IL-23/TH17轴，显着改善了小鼠咪喹莫夫触发的皮肤感染，证明SHP2是牛皮癣的潜在治疗靶标。
我们确定SHP2变构抑制剂TK-453，该抑制剂与SHP2具有更强的亲和力
共晶结构表明，TK-453占据了SHP2的变构袋
TK-453减轻小鼠类似牛皮癣的皮肤炎症
SHP2抑制剂为治疗牛皮癣提供了新的策略
生物化学；
SHP2 is the first oncogenic tyrosine phosphatase encoded by PTPN11, which plays a significant regulatory role in cancer and inflammation-related diseases. Although SHP2 allosteric inhibitors have been used in phase I/II clinical trials for solid tumors, whether SHP2 inhibition alleviates psoriasis remains unclear. Here we expressed and purified SHP2 related proteins, and established an enzyme activity screening system for different conformations of SHP2. We launched an iterative medicinal chemistry program and identified the lead compound, TK-453. Importantly, TK-453 possessed stronger affinity with SHP2 than SHP099, evidenced by the cocrystal structure of SHP2/TK-453, revealing that the additional aryl-S-aryl bridge in TK-453 induces a 1.8 Å shift of the dichlorophenyl ring and an approximate 20° deviation of the pyrazine ring plane relative to SHP099. Furthermore, TK-453 significantly ameliorated imiquimod-triggered skin inflammation in mice via inhibition of the IL-23/Th17 axis, proving that SHP2 is a potential therapeutic target for psoriasis. We identify a SHP2 allosteric inhibitor TK-453, which has a stronger affinity with SHP2 Cocrystal structure shows that TK-453 occupies the allosteric pocket of SHP2 TK-453 alleviates psoriasis-like skin inflammation in mice SHP2 inhibitor provides a new strategy for the treatment of psoriasis Biological sciences; Biochemistry; Medical biochemistry
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DOI：
10.1107/s0907444910051218
发表时间：
2011-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Bunkóczi G;Read RJ
通讯作者：
Read RJ
DOI：
10.1038/nri3477
发表时间：
2013-08
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1016/j.jaci.2017.07.004
发表时间：
2017-09
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Hawkes JE;Chan TC;Krueger JG
通讯作者：
Krueger JG
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH