MDM2-BCL-XL PROTACs enable degradation of BCL-XL and stabilization of p53.
MDM2-BCL-XL PROTACs enable degradation of BCL-XL and stabilization of p53.
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DOI：
10.15212/amm-2022-0022
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发表时间：
2022-07-21
期刊：
影响因子：
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通讯作者：
Wang, Wei
中科院分区：
文献类型：
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作者：
Chang, Mengyang;Gao, Feng;Wang, Wei
抑制或降解抗凋亡蛋白BCL-XL是一种可行的癌症治疗策略。尽管最近开发了用于降解BCL-XL的PROTAC，但E3连接酶仅限于常用的VHL和CRBN。本文中，我们报告了使用MDM 2作为E3连接酶用于降解BCL-XL的MDM 2-BCL-XL PROTAC的开发。设计、合成并体外评价了三种衍生自MDM 2抑制剂Nutlin-3（其也可以上调p53）和BCL-2/BCL-XL抑制剂ABT-263的具有不同接头长度的MDM 2-BCL-XL PROTAC。我们发现BMM 4在U87、A549和MV-4-11癌细胞系中表现出对BCL-XL的有效、选择性降解活性并稳定肿瘤抑制因子p53。此外，BMM 4和BCL-2抑制剂ABT-199的组合显示协同抗增殖活性。独特的双功能PROTAC为靶向蛋白质降解提供了一种替代策略。
Inhibition or degradation of anti-apoptotic protein BCL-XL is a viable strategy for cancer treatment. Despite the recent development of PROTACs for degradation of BCL-XL, the E3 ligases are confined to the commonly used VHL and CRBN. Herein we report the development of MDM2-BCL-XL PROTACs using MDM2 as E3 ligase for degradation of BCL-XL. Three MDM2-BCL-XL PROTACs derived from MDM2 inhibitor Nutlin-3, which can also upregulate p53, and BCL-2/BCL-XL inhibitor ABT-263 with different linker length were designed, synthesized, and evaluated in vitro. We found BMM4 exhibited potent, selective degradation activity against BCL-XL and stabilized tumor suppressor p53 in U87, A549 and MV-4-11 cancer cell lines. Moreover, combination of BMM4 and BCL-2 inhibitor ABT-199 showed synergistic antiproliferative activity. The unique dual-functional PROTACs offers an alternative strategy for targeted protein degradation.