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发现,开发和描述强效和选择性的USP11抑制剂

Forum Kayastha¹, Noah B Herrington², Anirban Roychowdhury¹

¹Division of Hematology, Oncology, and Palliative Care, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia; Section of Hematology and Oncology, Medicine Service, Richmond VA Cancer Center, Richmond Veteran Affairs Medical Center, Richmond, Virginia; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298.

Pharmacological research

|December 29, 2025

概括

针对USP11 (ubiquitin特定蛋白酶11) 非催化域的新抑制剂破坏瘤信号传递,并在淋巴瘤模型中表现出强大的抗瘤活性.

科学领域:

生物化学生物化学
分子生物学分子生物学
在瘤学瘤学.

背景情况:

脱基因酶 (DUB) 越来越多地被认为具有超越酶活性的作用,非催化域调节信号通路.
在淋巴瘤中,USP11 (ubiquitin-specific protease 11) 通过对eIF4B.等转化因子进行支架来稳定促生存的基因表达.
针对USP11的非催化功能,为侵袭性淋巴瘤提供了一种新的治疗策略.

研究的目的:

发现和描述USP11.1的第一类非催化抑制剂.
研究这些抑制剂影响瘤原体信号传递和细胞活性的机制.
在临床前淋巴瘤模型中评估USP11抑制的治疗潜力.

主要方法:

药理学指导的虚拟选,以识别USP11 UBL域结合剂.
生物化学测试以评估抑制剂结合和对USP11催化活性的影响.
细胞测试分析对eIF4B稳定,MYC驱动的翻译,DNA修复,平衡和亡的影响.
ортотоп性淋巴瘤异种移植模型,以评估RBF4.4的体内疗效和毒性.
转录组分析以探索分子作用机制.

主要成果:

RBF4和RBF11被确定为选择性,非催化性USP11抑制剂,结合UBL域.
抑制剂破坏eIF4B稳定和MYC驱动的翻译,而不会影响USP11的催化活性.
抑制USP11会诱导细胞亡,破坏DNA修复因子的稳定性,并重新调整平衡.
在EμMyc淋巴瘤模型中,RBF4显示出强大的抗瘤功效,减少瘤生长和转移,没有明显的毒性.
转录组数据揭示了EMT,免疫和代谢程序的重新连接,突出了USP11在瘤细胞可塑性中的作用.

结论:

USP11的UBL域是用于非催化抑制的可用药物标.
USP11作为瘤信号传递的关键支架,调节翻译和细胞身份.
非催化USP11抑制剂,如RBF4,代表了淋巴细胞恶性瘤的有希望的新治疗策略.
这项工作将DUB重新定义为结构信号平台,为癌症治疗开辟了新的途径.

关键词:

药物发现技术/药物发现技术药物目标/瘤蛋白和瘤抑制药物目标基因法规/转录后和翻译后控制血液学上的癌症/淋巴瘤

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