Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders.
Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders.
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DOI：
10.1039/d0sc00167h
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发表时间：
2020-04-07
期刊：
影响因子：
8.4
通讯作者：
Krönke J
中科院分区：
文献类型：
--
作者：
Steinebach C;Ng YLD;Sosič I;Lee CS;Chen S;Lindner S;Vu LP;Bricelj A;Haschemi R;Monschke M;Steinwarz E;Wagner KG;Bendas G;Luo J;Gütschow M;Krönke J
细胞周期蛋白依赖性激酶6 （CDK6）是细胞周期的重要调节因子。它与CDK4一起磷酸化并使视网膜母细胞瘤（Rb）蛋白失活。细胞周期蛋白依赖性激酶6 （CDK6）是细胞周期的重要调节因子。它与CDK4一起磷酸化并使视网膜母细胞瘤（Rb）蛋白失活。在肿瘤细胞中，CDK6经常上调，而帕博西尼等CDK4/6激酶抑制剂在乳腺癌和其他恶性肿瘤中具有高活性。除了其关键的催化功能外，CDK6的激酶无关作用也已被描述。因此，靶向降解CDK6可能比激酶抑制更有利。基于小脑（CRBN）配体沙利度胺结构的蛋白水解靶向嵌合体（PROTACs）最近被描述为降解靶标CDK4/6。然而，基于CRBN的PROTACs存在一些局限性，包括免疫调节药物（IMiDs）对Ikaros转录因子的剩余活性以及CRBN失活作为癌症耐药机制。在这里，我们系统地探索了CDK4/6 PROTACs的化学空间，通过定位不同的E3连接酶，并通过各种连接物将它们各自的小分子结合物连接到palbociclib。cdk6特异性PROTACs的光谱扩展到von Hippel Lindau （VHL）和细胞凋亡蛋白1抑制剂（cIAP1），它们是大多数癌细胞所必需的，因此不太可能失活。我们基于vhl的PROTAC系列包括对CDK6特异性或对CDK4和CDK6具有双重活性的化合物。基于iap的PROTACs导致CDK4/6和iap的联合降解，从而对癌细胞生长产生协同效应。我们的新型降解剂在人类和小鼠细胞中显示出有效和持久的降解活性，并抑制了几种白血病、骨髓瘤和乳腺癌细胞系的增殖。总之，我们表明基于VHL和iap的PROTACs是一种有吸引力的靶向降解癌症中CDK4/6的方法。
Cyclin-dependent kinase 6 (CDK6) is an important regulator of the cell cycle. Together with CDK4, it phosphorylates and inactivates retinoblastoma (Rb) protein. Cyclin-dependent kinase 6 (CDK6) is an important regulator of the cell cycle. Together with CDK4, it phosphorylates and inactivates retinoblastoma (Rb) protein. In tumour cells, CDK6 is frequently upregulated and CDK4/6 kinase inhibitors like palbociclib possess high activity in breast cancer and other malignancies. Besides its crucial catalytic function, kinase-independent roles of CDK6 have been described. Therefore, targeted degradation of CDK6 may be advantageous over kinase inhibition. Proteolysis targeting chimeras (PROTACs) structurally based on the cereblon (CRBN) ligand thalidomide have recently been described to degrade the targets CDK4/6. However, CRBN-based PROTACs have several limitations including the remaining activity of immunomodulatory drugs (IMiDs) on Ikaros transcription factors as well as CRBN inactivation as a resistance mechanism in cancer. Here, we systematically explored the chemical space of CDK4/6 PROTACs by addressing different E3 ligases and connecting their respective small-molecule binders via various linkers to palbociclib. The spectrum of CDK6-specific PROTACs was extended to von Hippel Lindau (VHL) and cellular inhibitor of apoptosis protein 1 (cIAP1) that are essential for most cancer cells and therefore less likely to be inactivated. Our VHL-based PROTAC series included compounds that were either specific for CDK6 or exhibited dual activity against CDK4 and CDK6. IAP-based PROTACs caused a combined degradation of CDK4/6 and IAPs resulting in synergistic effects on cancer cell growth. Our new degraders showed potent and long-lasting degrading activity in human and mouse cells and inhibited proliferation of several leukemia, myeloma and breast cancer cell lines. In conclusion, we show that VHL- and IAP-based PROTACs are an attractive approach for targeted degradation of CDK4/6 in cancer.
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影响因子：
11.2
作者：
Hines J;Lartigue S;Dong H;Qian Y;Crews CM
通讯作者：
Crews CM
影响因子：
10.5
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LaBaer, J;Garrett, MD;Harlow, E
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Harlow, E
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Winter, Georg E.
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