...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Cell cycle >Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212
【24h】

Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212

机译：Inaipridone家族的临床前评估临床阶段抗癌小分子ONC201，揭示了ONC212的有效的抗癌作用

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Anti-cancer small molecule ONC201 upregulates the integrated stress response (ISR) and acts as a dual inactivator of Akt/ERK, leading to TRAIL gene activation. ONC201 is under investigation in multiple clinical trials to treat patients with cancer. Given the unique imipridone core chemical structure of ONC201, we synthesized a series of analogs to identify additional compounds with distinct therapeutic properties. Several imipridones with a broad range of in vitro potencies were identified in an exploration of chemical derivatives. Based on in vitro potency in human cancer cell lines and lack of toxicity to normal human fibroblasts, imipridones ONC206 and ONC212 were prioritized for further study. Both analogs inhibited colony formation, and induced apoptosis and downstream signaling that involves the integrated stress response and Akt/ERK, similar to ONC201. Compared to ONC201, ONC206 demonstrated improved inhibition of cell migration while ONC212 exhibited rapid kinetics of activity. ONC212 was further tested in >1000 human cancer cell lines in vitro and evaluated for safety and anti-tumor efficacy in vivo. ONC212 exhibited broad-spectrum efficacy at nanomolar concentrations across solid tumors and hematological malignancies. Skin cancer emerged as a tumor type with improved efficacy relative to ONC201. Orally administered ONC212 displayed potent anti-tumor effects in vivo, a broad therapeutic window and a favorable PK profile. ONC212 was efficacious in vivo in BRAF V600E melanoma models that are less sensitive to ONC201. Based on these findings, ONC212 warrants further development as a drug candidate. It is clear that therapeutic utility extends beyond ONC201 to include additional imipridones.
机译：抗癌小分子ONC201上调了综合应力响应（ISR）并作为AKT / ERK的双灭弧剂，导致TRAIL基因激活。在多种临床试验中正在调查ONC201以治疗癌症患者。鉴于ONC201的独特泛啶酮核心化学结构，我们合成了一系列类似物以鉴定具有不同治疗性质的额外化合物。在化学衍生物的探索中确定了具有广泛体外效力的几种Imipridones。基于人体癌细胞系中的体外效力以及对正常人体成纤维细胞的缺乏毒性，优先考虑Imipridones ONC206和ONC212进行进一步研究。两种类似物抑制菌落形成，诱导诱导凋亡和下游信号，涉及综合应力响应和AKT / ERK，类似于ONC201。与ONC201相比，ONC206表现出对细胞迁移的改善抑制，而ONC212表现出快速的活性动力学。在体外，在> 1000人癌细胞系中进一步测试了ONC212，并在体内评估了安全性和抗肿瘤疗效。 ONC212在实体肿瘤和血液恶性恶性肿瘤上表现出纳米摩尔浓度的广谱效果。皮肤癌作为肿瘤型，相对于ONC201具有改善的疗效。口服施用的ONC212显示体内有效的抗肿瘤作用，宽阔的治疗窗口和有利的PK轮廓。 ONC212在BRAF V600E黑色素瘤模型中的体内有效，对ONC201不太敏感。根据这些调查结果，ONC212认证作为毒品候选人进一步发展。很明显，治疗效果超越ONC201以包括额外的IMIPRIDONES。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号