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  2. Analysis on benzothiazole necroptosis inhibitors with chiral substitutions in the solvent-accessible region of RIP kinase domain

Analysis on benzothiazole necroptosis inhibitors with chiral substitutions in the solvent-accessible region of RIP kinase domain

  • Bioorg Chem. 2023 Jun 1;137:106647. doi: 10.1016/j.bioorg.2023.106647.
Hongming Shao 1 Lijuan Xu 1 Gechang Li 2 Shuyu Wang 3 Ting Han 4 Chunlin Zhuang 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
  • 2 School of Pharmacy, Guangdong Pharmaceutical University, Guangdong 510006, China.
  • 3 School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.
  • 4 School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: hanting@smmu.edu.cn.
  • 5 School of Pharmacy, Second Military Medical University, Shanghai 200433, China; School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China. Electronic address: zclnathan@163.com.
Abstract

Receptor-interacting protein kinase 1 (RIPK1) and RIPK3, two imperative targets of the Necroptosis pathway, are associated with various inflammatory-related diseases. Regulating kinase activity with inhibitors has been confirmed as a promising strategy for inflammation treatment. However, most of the reported type I and II kinase inhibitors of RIPK1 and RIPK3, including benzothiazole compounds discovered by our group, have selective limitations due to interaction with ATP-binding pockets. Fortunately, a solvent exposure E0 region of the kinase domain, which extends into the linker region, has been reported to be related to the potency and selectivity of inhibitors. Hence, based on our previous study, a series of benzothiazole Necroptosis inhibitors with chiral substitutions in the linker region were developed to investigate RIPK1/3 inhibitory potency. The results showed a 2-to 6-fold increase in anti-necroptotic activity for these chiral compounds. The improved selectivity on RIPK1 or RIPK3 was demonstrated on different derivatives. Predicted binding conformations of enantiomers with RIPK1/3 gave an explanation for their activity differences, guiding further rational design of chiral Necroptosis inhibitors.

Keywords

Benzothiazole; Chiral effects; Necroptosis; RIPK1; RIPK3.

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