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新的Ref-1/APE1向抑制剂显示出在多种癌症类型中改善了临床应用的效力

Silpa Gampala¹, Hye-Ran Moon², Randall Wireman³

¹Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Pharmacological research

|February 4, 2024

概括

研究人员开发了针对AP内核酶-1/Redox因子-1 (APE1/Ref-1) 的新型,强有力的抑制剂,用于癌症治疗. 这些第二代化合物比第一代药物显著提高了疗效和安全性,为临床转化铺平了道路.

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:

在侵袭性癌症中,AP内核酶-1/氧化因子-1 (APE1/Ref-1) 过度表达.
Ref-1的氧化还原活性影响关键的癌症信号通路,包括NFκB和HIF1α.
针对Ref-1的氧化还原功能是一个有前途的治疗策略.

研究的目的:

识别和验证Ref-1氧化还原功能的强效,选择性第二代抑制剂.
与第一代化合物APX3330.0相比,开发具有更强效和更安全的类似物.
评估这些抑制剂在固体瘤中的治疗潜力.

主要方法:

进行了结构-活性关系 (SAR) 研究.
试验室试验包括药代动力学 (PK) 分析,代谢稳定性 (S9分数),在中预测ADMET,WaterLOGSY NMR和细胞活力试验.
在体内表征涉及3D细胞杀死试验,药理动力学标记分析和全球蛋白质组学.

主要成果:

新的Ref-1抑制剂表现出比APX3330强度大5至10倍的功效.
化合物表现出有利的PK配置文件和可比或改进的安全性.
在体内研究证实了Ref-1抑制和治疗疗效的潜力.

结论:

强大的第二代Ref-1氧化还原抑制剂被成功识别和表征.
这些化合物在治疗固体瘤方面显示出显著的前景.
根据有效性和安全性数据,需要进一步的临床开发.

关键词:

癌症癌症癌症癌症缺氧诱导因子1 (HIF1α)MPNST MPNST 的意思是新型向性抑制剂新型向性抑制剂核因子卡帕B (NFκB) 的核因子我们的PDAC是PDAC.强度强度强度强度 Ref-1 氧化还原功能的功能

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