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Necroptosis is a controlled method of cell necrosis.
Receptor-interacting kinase 1 (RIPK1) plays a key role in the death receptor-mediated pathway of programmed cell necrosis
.
More and more studies have shown that the development of highly active and selective inhibitors targeting RIPK1 can provide new approaches for the treatment of inflammatory diseases, neurological diseases, tumors, and sepsis
.
Receptor-interacting kinase 1 (RIPK1) plays a key role in the death receptor-mediated pathway of programmed cell necrosis
.
More and more studies have shown that the development of highly active and selective inhibitors targeting RIPK1 can provide new approaches for the treatment of inflammatory diseases, neurological diseases, tumors, and sepsis
.
The research team of Zhou Bing, Tang Wei, and Xu Yechun of Shanghai Institute of Materia Medica, Chinese Academy of Sciences started with the RIPK1 allosteric inhibitor GSK2982772 in clinical phase II, and carried out structure-based rationalization based on the characteristics of the binding mode of the small molecule and the target protein.
Drug design has resulted in a class of highly active and selective RIPK1 inhibitors acting on the double pockets
.
On December 16, 2021, related research work was published online in Angew.
Chem.
Int.
Ed with the title "Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis"
.
Drug design has resulted in a class of highly active and selective RIPK1 inhibitors acting on the double pockets
.
On December 16, 2021, related research work was published online in Angew.
Chem.
Int.
Ed with the title "Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis"
.
In the U937 cell necrosis model induced by TNFα, compared with the positive GSK2982772, the inhibitory activity of these derivatives is increased by more than 10 times, and the IC50 value is less than 0.
5 nM
.
Further crystallographic studies showed that compound 20/21 occupied both the allosteric pocket and the ATP binding pocket, which reasonably explained the increase in inhibitory activity
.
5 nM
.
Further crystallographic studies showed that compound 20/21 occupied both the allosteric pocket and the ATP binding pocket, which reasonably explained the increase in inhibitory activity
.
In the kinase profile test, at a test concentration of 1 μM, compound No.
21 showed excellent kinase selectivity
.
In mouse pharmacokinetic studies, the compound showed good pharmacokinetic properties, with oral bioavailability >99%
.
In the TNFα-induced systemic inflammatory response model (SIRS), the compound was significantly better than the positive reference GSK2982772 in protecting the body temperature of mice
.
In the LPS-induced sepsis model, compound 21 showed significantly better efficacy than positive in terms of restoring body temperature, survival rate, and inhibiting cytokine storm in mice
.
21 showed excellent kinase selectivity
.
In mouse pharmacokinetic studies, the compound showed good pharmacokinetic properties, with oral bioavailability >99%
.
In the TNFα-induced systemic inflammatory response model (SIRS), the compound was significantly better than the positive reference GSK2982772 in protecting the body temperature of mice
.
In the LPS-induced sepsis model, compound 21 showed significantly better efficacy than positive in terms of restoring body temperature, survival rate, and inhibiting cytokine storm in mice
.
In summary, the study revealed a class of highly active and selective RIPK1 inhibitors with a novel mode of action, which is expected to provide new strategies for the treatment of systemic inflammatory diseases and neurological diseases
.
.
Doctoral students Yang Xiangbo and Lu Huimin of the Shanghai Institute of Materia Medica, and Xie Hang, a Ph.
D candidate in the joint training of Shanghai Institute of Materia Medica-Nanjing University of Traditional Chinese Medicine, are the first authors of the article.
Researchers Zhou Bing, Researchers Tang Wei and Associate Researchers Su Haixia are the co-corresponding authors of this article
.
D candidate in the joint training of Shanghai Institute of Materia Medica-Nanjing University of Traditional Chinese Medicine, are the first authors of the article.
Researchers Zhou Bing, Researchers Tang Wei and Associate Researchers Su Haixia are the co-corresponding authors of this article
.
This work was funded by the National Natural Science Foundation of China and the Shanghai Municipal Science and Technology Commission
.
.
Full text link: https://onlinelibrary.
wiley.
com/doi/epdf/10.
1002/anie.
202114922
wiley.
com/doi/epdf/10.
1002/anie.
202114922
Fig.
20/21 compound binding mode analysis
20/21 compound binding mode analysis
(Contributed by: Zhou Bing/Tang Wei/Xu Yechun's research group)
