Hydrogen Peroxide Inducible JAK3 Covalent Inhibitor: Prodrug for the Treatment of RA with Enhanced Safety Profile,ACS Medicinal Chemistry Letters

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Hydrogen Peroxide Inducible JAK3 Covalent Inhibitor: Prodrug for the Treatment of RA with Enhanced Safety Profile
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-10-05 , DOI: 10.1021/acsmedchemlett.0c00323
Qichao Bao _{1,

2} , Liangying Zhang _{1,

2} , Nan Wang ₃ , Brian Gabet ₃ , Weikang Yang _{1,

2} , Xingyang Gao _{1,

2} , Qidong You _{1,

2} , Zhengyu Jiang _{1,

2}

Affiliation

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.

中文翻译：

过氧化氢诱导型 JAK3 共价抑制剂：具有增强安全性的治疗 RA 的前药

Janus 激酶 (JAK) 的选择性抑制是药物发现中的一种新兴策略。针对 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。设计并合成了一种已知的对 H ₂ O ₂敏感的 JAK3 共价抑制剂的前药，并在 RA（类风湿性关节炎）的 CIA（胶原诱导性关节炎）小鼠模型中评估了其治疗效果。前药策略依赖于引入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随机共价结合。结果表明，在病理生理浓度的H ₂ O下，前药可以被激活和释放。₂ . 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 模型中显示出类似的治疗效果，但显着地表现出较低的毒性和较大的治疗窗口。

更新日期：2020-11-12

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