c-Myc-Targeting PROTAC Based on a TNA-DNA Bivalent Binder for Combination Therapy of Triple-Negative Breast Cancer
c-Myc-Targeting PROTAC Based on a TNA-DNA Bivalent Binder for Combination Therapy of Triple-Negative Breast Cancer
复制标题
DOI：
10.1021/jacs.3c02619
复制
发表时间：
2023-04-17
影响因子：
15
通讯作者：
Guan, Xiaoxiang
中科院分区：
文献类型：
--
作者：
Li, Xintong;Zhang, Ze;Guan, Xiaoxiang
三阴性乳腺癌（TNBC）具有高度侵袭性，临床预后差，无靶向治疗。c-Myc蛋白是一种主转录因子，也是TNBC的潜在治疗靶点。在这项研究中，我们开发了一种基于TNA （threose核酸）和DNA的PROteolysis TArgeting Chimera（蛋白水解靶向嵌合体），可以有效地靶向和降解c-Myc。在体外选择TNA适配体结合c-Myc/Max异源二聚体，并附加到E-box DNA序列上，形成高亲和力，生物稳定的二价结合物。TNA-E box-pomalidomide （TEP）偶联物在体外特异性降解内源性c-Myc/Max，抑制TNBC细胞增殖，并使TNBC细胞对周期蛋白依赖性激酶抑制剂palbociclib增敏。在小鼠TNBC模型中，TEP和帕博西尼联合治疗能有效抑制肿瘤生长。这项研究为TNBC的化学生物学研究和治疗干预提供了一种有前途的基于核酸的PROTAC模式。
Triple-negative breast cancer (TNBC) is highly aggressive with a poor clinical prognosis and no targeted therapy. The c-Myc protein is a master transcription factor and a potential therapeutic target for TNBC. In this study, we develop a PROTAC (PROteolysis TArgeting Chimera) based on TNA (threose nucleic acid) and DNA that effectively targets and degrades c-Myc. The TNA aptamer is selected in vitro to bind the c-Myc/Max heterodimer and appended to the E-box DNA sequence to create a high-affinity, biologically stable bivalent binder. The TNA-E box-pomalidomide (TEP) conjugate specifically degrades endogenous c-Myc/Max, inhibits TNBC cell proliferation, and sensitizes TNBC cells to the cyclin-dependent kinase inhibitor palbociclib in vitro. In a mouse TNBC model, combination therapy with TEP and palbociclib potently suppresses tumor growth. This study offers a promising nucleic acid-based PROTAC modality for both chemical biology studies and therapeutic interventions of TNBC.