Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer.
Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer.
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Homo-PROTAC 介导 MDM2 自杀治疗非小细胞肺癌
DOI：
10.1016/j.apsb.2020.11.022
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Sheng C
中科院分区：
文献类型：
--
作者：
He S;Ma J;Fang Y;Liu Y;Wu S;Dong G;Wang W;Sheng C
MDM2-p53抑制剂的剂量相关不良反应在临床安全抗癌药物的开发中引起了极大的关注。在这里，我们报告了一种前所未有的HOMO-PROTAC策略，以更有效地破坏MDM2-P53相互作用。设计理念的灵感来自于亚化学计量催化PROTAC能够降解不需要的蛋白质的能力，以及MDM2作为E3泛素连接酶和与肿瘤抑制因子P53结合的蛋白的双重功能。新的HOMO-PROTAC旨在诱导MDM2的自我降解。研究结果表明，在A549非小细胞肺癌细胞中，PROTAC 11a有效地二聚具有高竞争性结合活性的MDM2，并诱导蛋白酶体依赖的MDM2的自我降解。此外，值得注意的是，对映体11a-1在A549裸鼠移植瘤模型中显示出很强的体内抗肿瘤活性，这是Homo-PROTAC具有体内治疗效力的第一个例子。这项研究证明了Homo-PROTAC作为一种替代的化学工具来敲除致癌的MDM2的潜力，这可能被开发成一种安全的癌症治疗方法。首次证明了一种具有体内和体外抗肿瘤活性的Homo-PROTAC策略。这一方法可能为克服MDM2-P53抑制剂在临床抗癌药物开发中与剂量相关的不良反应的瓶颈提供机会。
The dose-related adverse effects of MDM2‒P53 inhibitors have caused significant concern in the development of clinical safe anticancer agents. Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2‒P53 interaction. The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53. The new homo-PROTACs are designed to induce self-degradation of MDM2. The results of the investigation have shown that PROTAC 11a efficiently dimerizes MDM2 with highly competitive binding activity and induces proteasome-dependent self-degradation of MDM2 in A549 non-small cell lung cancer cells. Furthermore, markedly, enantiomer 11a-1 exhibits potent in vivo antitumor activity in A549 xenograft nude mouse model, which is the first example of homo-PROTAC with in vivo therapeutic potency. This study demonstrates the potential of the homo-PROTAC as an alternative chemical tool for tumorigenic MDM2 knockdown, which could be developed into a safe therapy for cancer treatment. “Suicide” cleavage of MDM2: a homo-PROTAC strategy possessing effective in vitro and in vivo antitumor activities is demonstrated for the first time. The approach may offer an opportunity to overcome the bottleneck of the dose-related adverse effects of MDM2‒P53 inhibitors in the development of clinical anticancer agents.
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