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一级强大,双HDAC6 / 蛋白质酶抑制剂缺乏胺酸动机:发现了新型抗多发性骨髓瘤剂

Alexandria M Chan¹, Brandon D Lowe¹, Andrea L Cottingham¹

¹Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, Maryland 21201, United States.

ACS medicinal chemistry letters

|January 14, 2026

概括

研究人员开发了新的双重抑制剂,其向素脱乙酶6 (HDAC6) 和蛋白酶体. 这些化合物在治疗多发性骨髓瘤 (MM) 方面表现有前途,通过提供比现有疗法更好的选择性和效力.

科学领域:

药用化学医学化学
在瘤学瘤学.
分子生物学分子生物学

背景情况:

复发性/耐药性多发性骨髓瘤 (MM) 是一个重大的临床挑战.
目前的基因素脱乙酶 (HDAC) 抑制剂由于缺少异构体选择性和使用酸结合群而表现出非目标效应和潜在的突变性.
与HDAC抑制剂 (例如,利可林) 和蛋白酶体抑制剂 (例如,博特佐米布) 的联合治疗在MM中显示出临床前景.

研究的目的:

为了设计针对HDAC6和蛋白酶体的新型双重抑制剂.
克服现有的HDAC抑制剂的局限性,包括非目标效应和潜在的致变性.
确定用于治疗多发性骨髓瘤的强效和选择性双重抑制剂.

主要方法:

设计和合成使用HDAC6选择性基因和胺酸替代品的双HDAC6/蛋白酶体抑制剂.
将这些图案移植到博雷佐米布/伊克萨佐米布的电友玻酸弹头上.
在无细胞试验中对蛋白质体活性抑制和HDAC异型选择性的化合物的评估.
对多发性骨髓瘤细胞生长的抑制作用的评估.

主要成果:

合成了几种双重HDAC6/蛋白酶体抑制剂,并证明强烈抑制了基米托里类 (CL) 蛋白酶体活性,与博特佐米布相当.
许多化合物对HDAC6表现出对HDAC1.1的预测选择性.
多种双重抑制剂显示出对抗多发性骨髓瘤细胞生长的亚微分子功效.
化合物AMC-3-030,具有O- ((N-phenylcarbamoyl) -hydroxamate结合组,成为一个有希望的候选者.

结论:

新的双HDAC6 / 蛋白酶体抑制剂已经成功设计.
这些化合物在选择性和强度方面为多发性骨髓瘤治疗提供了潜在的优势.
在多发性骨髓瘤治疗方面,AMC-3-030代表了进一步临床前发展的有希望的领先因素.

关键词:

癌症癌症癌症癌症在 HDAC6 中.博尔特佐米布 (Bortezomib) 是一种药物.多发性骨髓瘤是多发性骨髓瘤的一种疾病.多种药理学多种药理学蛋白质酶体蛋白质组是什么

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