Shao Hongming, Xu Lijuan, Li Gechang, Wang Shuyu, Han Ting, Zhuang Chunlin
School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
School of Pharmacy, Guangdong Pharmaceutical University, Guangdong 510006, China.
Bioorg Chem. 2023 Aug;137:106647. doi: 10.1016/j.bioorg.2023.106647. Epub 2023 Jun 1.
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.
受体相互作用蛋白激酶1（RIPK1）和RIPK3是坏死性凋亡途径的两个重要靶点，与多种炎症相关疾病有关。用抑制剂调节激酶活性已被确认为一种有前景的炎症治疗策略。然而，大多数已报道的RIPK1和RIPK3的I型和II型激酶抑制剂，包括我们小组发现的苯并噻唑化合物，由于与ATP结合口袋相互作用而存在选择性限制。幸运的是，据报道，延伸至连接区的激酶结构域的一个溶剂暴露E0区域与抑制剂的效力和选择性有关。因此，基于我们之前的研究，开发了一系列在连接区具有手性取代的苯并噻唑坏死性凋亡抑制剂，以研究RIPK1/3抑制效力。结果表明，这些手性化合物的抗坏死性凋亡活性提高了2至6倍。在不同衍生物上证明了对RIPK1或RIPK3的选择性提高。对映体与RIPK1/3的预测结合构象解释了它们的活性差异，为手性坏死性凋亡抑制剂的进一步合理设计提供了指导。
