一个螺旋环候选ADRM1/RPN13抑制剂Up284的发展和抗癌特性
Ravi K Anchoori1,2,3, Vidyasagar Anchoori3,4, Brandon Lam2
1Department of Oncology, Johns Hopkins University, Baltimore, MD, United States of America.
PloS one
|June 14, 2023
概括
一种新型的蛋白酶体抑制剂Up284通过向RPN13显示强大的抗癌活性,对抗固体瘤和多发性髓瘤. 它在临床前癌症模型中表现出改善的类似药物的特性和治疗功效.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 博尔特佐米布对多发性骨髓瘤有效,但由于毒性和耐药性,对固体瘤的有效性有限.
- 针对ADRM1/RPN13的替代蛋白酶体抑制剂正在开发中,但现有的候选药物具有低于最佳的类似药物的特性.
研究的目的:
- 描述Up284,一种具有螺旋碳核的新型RPN13抑制剂,旨在克服以前蛋白酶体抑制剂的局限性.
- 在各种癌症模型中评估Up284的抗癌活性,作用机制和药理动力学特性.
主要方法:
- 对Up284的有效性进行了测试,对各种癌症细胞系进行了测试,包括对博雷佐米布耐药的细胞系.
- 研究了细胞毒性的机制,包括对线粒体功能,活性氧物种,蛋白质聚合和亡的影响.
- 在小鼠中进行了药理动力学和药理动力学研究,以及在多种临床前癌症模型中进行治疗疗效评估.
主要成果:
- Up284对卵巢,乳腺,结肠,宫,前列腺,多发性骨髓瘤和质母细胞瘤细胞系表现出广泛的细胞毒性,包括对博特佐米布和西斯普拉丁耐药的细胞系.
- Up284诱导了线粒体功能障碍,增加了活性氧物种,蛋白质聚合物的积累,未折叠的蛋白质反应和亡.
- Up284与西斯普拉丁显示出协同作用,增强了抗原呈现,良好的药理动力学,长时间的蛋白质酶抑制在体内,并且在小鼠中耐受良好,在卵巢癌模型中显示出治疗活性.
结论:
- Up284是一种有前途的新型蛋白酶体抑制剂,具有强大的抗癌活性和改进的类似药物的特性.
- 在临床前模型中Up284的独特机制和疗效需要进一步研究固体瘤和多发性骨髓瘤治疗.
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