时间标签：数据日期 2026-10-31 · 生成时间 2026-11-01 05:30（Asia/Shanghai）｜ 检索窗口 PubMed edat 2026/10/28–2026/10/31 ｜ 情报发生日期 2026-10-31
研究问题
Inhibition of human ClpP using chemical agents, however, remains a challenge.
方法
All animal work was conducted at the UHN Animal Resource Center (ARC) under approved Animal Use Protocols: AUP#7040 for PK studies and AUP#1251 for the mouse models of leukemia.；Target engagement in cells was assessed using a cellular thermal shift assay (CETSA) with the inCELL Detection Kit (Eurofins DiscoverX).；Plates were then heated on a heating block at 67 °C for 3 min to induce protein denaturation, followed by cooling at 25 °C for 3 min.；To commence the proteasome activity assay, cells are first harvested via centrifugation at 1200 r.p.m. at room temperature.
核心结论
We identified a quinazolinone derivative as an initial hit with an IC50 of 124 nM (95% C.I. 90–160 nM) (Fig. ).；Maintaining the quinazolinone moiety was essential, and a 7-chloro substituent significantly enhanced potency.；The scaffold core was sensitive to ring size changes or substitutions, and the presence of the trifluoromethyl group was essential. ‖ 结论：Our findings indicate that allosteric ClpP inhibition may offer a viable therapeutic approach in AML.
局限
Future studies will determine whether the in vivo efficacy was due to inhibition of ClpP, PRKCI, a combination of these, or additional targets.；As OICR18704 binds ClpP outside the active site, conventional screening approaches for assessing specificity may not capture the additional targets of the inhibitor.
对本项目的价值
★★☆☆☆ 相关范围内，作为背景与横向对照收录。
全文来源
PMC JATS 全文（正文 59,341 字符，已过标题/DOI 逐字归属校验）
原文题录
- 英文标题：Allosteric inhibition of human mitochondrial ClpP by hijacking the dordaviprone (ONC201) binding site.
- 期刊与标识：Nat Commun · PMID 42946762 · DOI 10.1038/s41467-026-78140-5
A 级证据分级：A 级（同行评议人体研究）
本文属人体研究证据，但需注意：观察性或小样本干预的结论不等于已证实临床获益；效应量与长期安全性仍需更大规模、更长随访的试验验证。
关于本文的文献来源：本站依据 IMA 知识库「五刊监控·深度文献卡片」撰写，依据已获取的期刊全文（方法、样本量与结论已回到原文核对）；未能获取全文的同批条目另行标注「摘要级」，全程未做任何数值推算补全。