Hydrogen Peroxide Inducible JAK3 Covalent Inhibitor: Prodrug for the Treatment of RA with Enhanced Safety Profile
Hydrogen Peroxide Inducible JAK3 Covalent Inhibitor: Prodrug for the Treatment of RA with Enhanced Safety Profile
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过氧化氢诱导型 JAK3 共价抑制剂：用于治疗 RA 的前药，安全性更高
DOI：
10.1021/acsmedchemlett.0c00323
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发表时间：
2020-11-12
影响因子：
4.2
通讯作者：
Jiang, Zhengyu
中科院分区：
文献类型：
--
作者：
Bao, Qichao;Zhang, Liangying;Jiang, Zhengyu
选择性抑制Janus激酶（JAK）是一种新兴的药物发现策略。靶向JAK3中独特半胱氨酸的共价抑制剂在JAK家族成员中表现出超选择性。然而，安全性和组织特异性问题仍然存在。设计并合成了已知的对H2O2敏感的JAK 3共价抑制剂的前药，并在RA（类风湿性关节炎）的CIA（胶原诱导的关节炎）小鼠模型中评价了其治疗效果。前药策略依赖于引入过氧化氢敏感的硼酸酯触发基团，以避免与生物大分子中的硫醇官能团随机共价结合。结果表明，在病理生理浓度的H2O2作用下，前体药物可被激活并释放。此外，前药表现出对生理环境的稳定性。与母体化合物相比，前药在CIA模型中显示出相似的治疗效果，但明显表现出较低的毒性和较大的治疗窗。
Selective inhibition of Janus kinases (JAKs) is an arising strategy in drug discovery. Covalent inhibitors targeting a unique cysteine in JAK3 exhibit ultraselectivity among JAK family members. However, safety and tissue specific concerns still remain. A prodrug of a known JAK3 covalent inhibitor sensitive to H2O2 was designed and synthesized and its therapeutic effect was evaluated in the CIA (collagen-induced arthritis) mice model of RA (rheumatoid arthritis). The prodrug strategy relied on the introduction of a hydrogen peroxide-sensitive borate trigger group to avoid random covalent binding to thiol functionalities in biomacromolecules. The results show that the prodrug can be activated and released under pathophysiological concentration of H2O2. In addition, the prodrug demonstrated stability to the physiological environment. In comparison to the parent compound, the prodrug showed a similar therapeutic effect in the CIA model but notably exhibited lower toxicity and a larger therapeutic window.