过氧化氢诱导型JAK3共价抑制剂：具有更高安全性的类风湿关节炎治疗前体药物。
Hydrogen Peroxide Inducible JAK3 Covalent Inhibitor: Prodrug for the Treatment of RA with Enhanced Safety Profile.
作者信息
Bao Qichao, Zhang Liangying, Wang Nan, Gabet Brian, Yang Weikang, Gao Xingyang, You Qidong, Jiang Zhengyu
机构信息
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
出版信息
ACS Med Chem Lett. 2020 Oct 5;11(11):2182-2189. doi: 10.1021/acsmedchemlett.0c00323. eCollection 2020 Nov 12.
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 HO 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 HO. 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.
选择性抑制Janus激酶（JAKs）是药物研发中一种新兴的策略。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。设计并合成了一种对过氧化氢（HO）敏感的已知JAK3共价抑制剂的前药，并在类风湿性关节炎（RA）的胶原诱导性关节炎（CIA）小鼠模型中评估了其治疗效果。前药策略依赖于引入对过氧化氢敏感的硼酸盐触发基团，以避免与生物大分子中的硫醇官能团发生随机共价结合。结果表明，该前药可以在HO的病理生理浓度下被激活并释放。此外，该前药对生理环境具有稳定性。与母体化合物相比，该前药在CIA模型中显示出相似的治疗效果，但毒性明显较低，治疗窗口更大。
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