确定Pyrido[3,4-d]pyrimidine衍生物作为RIPK3-介导的亡抑制剂
Namkyoung Kim1, Chan-Jung Park1, Younghoon Kim1
1KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea; Severance Biomedical Science Institute, Graduate School of Medicinal Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
European journal of medicinal chemistry
|July 26, 2023
概括
研究人员开发了新的pyrido[3,4-d]pyrimidine衍生物,通过准RIPK3-介导的MLKL酸化来抑制亡. 化合物20显示出有希望的RIPK3选择性和有效性,可以减少炎症和癌细胞入侵.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 死细胞灭绝,一种被编程的细胞死亡途径,是由RIPK3介导的MLKL酸化驱动的,并且与炎症性疾病有关.
- 向死的治疗为各种病理状况提供了治疗潜力.
研究的目的:
- 设计和合成新型的pyrido[3,4-d]pyrimidine衍生物作为死亡灭的抑制剂.
- 评估这些化合物对RIPK3和MLKL的抑制活性和选择性.
主要方法:
- 合成pyrido[3,4-d]pyrimidine衍生物的合成.
- 结构与活动关系 (SAR) 研究.
- 生物化学激酶试验和基于细胞的试验 (HT-29,AsPC-1细胞).
- 在体内研究以评估系统性炎症反应.
主要成果:
- 化合物20在HT-29细胞中表现出与GSK872相比的RIPK3-介导的pMLKL抑制活性.
- 与GSK872.2相比,化合物20对RIPK3比RIPK1具有更高的选择性.
- 20通过阻碍MLKL寡合化和抑制癌细胞迁移和入侵来抑制亡.
- 20在体内缓解TNFα诱导的系统性炎症反应.
结论:
- 皮里多[3,4-d] 皮里米丁衍生物,特别是化合物20是死亡灭的有效抑制剂.
- 化合物20显示出作为治疗性剂的潜力,用于与亡和炎症相关的疾病.
- 这项研究为设计新型RIPK3-选择性亡抑制剂提供了洞察力.
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