通过与氨酸反应化合物结合的JAK2的Allosteric抑制,这些化合物结合了伪激酶域
Marina C Primi1, Maurício T Tavares1, John M Hatcher1
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02215, United States.
European journal of medicinal chemistry
|October 30, 2025
概括
研究人员开发了针对JAK2伪激酶域的新型化合物,为骨髓增殖性瘤 (MPNs) 提供了新的策略. 这些化合物表现出全抑制,为潜在的突变选择性JAK2疗法铺平了道路.
科学领域:
- 生物化学 生物化学
- 药用化学 医学化学
- 在瘤学瘤学.
背景情况:
- 简氏酶2 (JAK2) 中的V617F突变是髓增殖性瘤 (MPNs) 的关键驱动因素.
- 现有的JAK2抑制剂向激酶域,缺乏对突变形式的选择性,限制了有效性和耐受性.
- 作为V617F突变的所在地,JAK2伪激酶域是开发突变选择性抑制剂的潜在目标.
研究的目的:
- 设计和表征新型化合物,选择性地准JAK2伪激酶域.
- 调查抑制的机制,包括全效应和共价变异.
- 为提供针对伪激酶域作为MPN治疗策略的概念证明.
主要方法:
- 设计和合成针对JAK2伪激酶域中的独特残留物 (Cys675,Lys677) 的共价抑制剂.
- 使用纯化的酶结构进行生物化学测定,以评估抑制效能和选择性.
- 同结晶学以确定抑制剂的结合方式.
- 液体染色学-并联质谱学 (LC-MS/MS) 来确认共价变异.
主要成果:
- 选择的化合物强烈抑制了含有伪激酶的JAK2结构,相对节省了分离的激酶域,表明了全抑制.
- 化合物20是一种氨酸反应抑制剂,证明了强大的全长JAK2抑制 (IC50 = 160nM).
- 同晶体结构证实了化合物20在JAK2伪激酶域中的对Lys677的共价结合.
结论:
- JAK2 伪激酶域可以作为所有菌抑制的目标.
- 在JAK2伪激酶域中对Lys677的共价向是可行的.
- 这些发现支持开发突变选择性JAK2抑制剂,通过向MPN治疗的伪激酶域.
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