针对癌症点Jumonji-C域含有蛋白6的分析抑制剂架构
Thomas P Corner1, Eidarus Salah1, Anthony Tumber1
1Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
ChemMedChem
|October 31, 2025
概括
研究人员开发了一种新的测定方法,以寻找JMJD6抑制剂用于前列腺癌治疗. 一些用于其他疾病的现有药物有效抑制JMJD6,这表明了新的治疗途径.
科学领域:
- 生物化学 生化学
- 分子生物学分子生物学
- 在瘤学瘤学.
背景情况:
- 含有 Jumonji-C 域的蛋白6 (JMJD6) 是一种参与翻译后修改的人类酶.
- 失调的JMJD6活性与雄激素受体结合变异7 (AR-V7) 的上调相关,这是一个驱动前列腺癌抗雄激素疗法耐药性的机制.
- 由于JMJD6在治疗耐药性方面的作用,被认为是前列腺癌的潜在治疗标.
研究的目的:
- 建立和验证一种可靠的测定方法,用于选小分子抑制剂的孤立JMJD6.6.
- 识别具有开发选择性JMJD6抑制剂潜力的新型化学支架.
- 调查已知JMJD6抑制剂和临床药物的抑制活性,针对孤立的JMJD6.
主要方法:
- 开发结合质谱法 (SPE-MS) 试验的固相提取方法,用于监测JMJD6的催化活性.
- 使用开发的SPE-MS测定方法对之前报告的JMJD6抑制剂 (WL12,SKLB325,化合物7p) 的查.
- 对临床使用的含蛋白 (PHD) 抑制剂 (Enarodustat,Desidustat) 对单独的JMJD6.6进行体外抑制作用的评估.
主要成果:
- 开发的SPE-MS试验提供了一种可靠的方法来评估小分子抑制JMJD6.
- 以前报告的JMJD6抑制剂在体外显示出有限的疗效.
- 一些临床PHD抑制剂,特别是Enarodustat和Desidustat,表现出强烈的抑制孤立的JMJD6.
- 这表明JMJD6抑制可能是这些临床使用的PHD抑制剂的非目标效应.
结论:
- 这项研究提供了一种有效的测定方法,用于识别和表征JMJD6抑制剂.
- 确定了开发选择性和细胞透性JMJD6抑制剂的有吸引力的化学支架.
- 这些发现表明,JMJD6抑制可能是临床环境中使用某些PHD抑制剂的意外后果,需要进一步调查.
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