PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase.
PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase.
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DOI：
10.1038/s41589-020-00652-y
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发表时间：
2020-11
影响因子：
14.8
通讯作者：
Wolf E
中科院分区：
文献类型：
--
作者：
Adhikari B;Bozilovic J;Diebold M;Schwarz JD;Hofstetter J;Schröder M;Wanior M;Narain A;Vogt M;Dudvarski Stankovic N;Baluapuri A;Schönemann L;Eing L;Bhandare P;Kuster B;Schlosser A;Heinzlmeir S;Sotriffer C;Knapp S;Wolf E
有丝分裂激酶AURORA-A对细胞周期进展至关重要，被认为是优先癌症靶点。虽然AURORA-A的催化活性对其有丝分裂功能至关重要，但最近的报道表明了一种额外的非催化功能，这是常规小分子难以靶向的。因此，我们通过将AURORA-A的临床激酶抑制剂与E3连接酶结合分子（例如沙利度胺）连接，开发了一系列化学降解剂（PROTAC）。一种降解剂诱导AURORA-A快速、持久和高度特异性降解。此外，我们发现降解复合物通过AURORA-A和CEREBLON之间的协同结合而稳定。降解剂介导的AURORA-A消耗导致S期缺陷，这不是激酶抑制后观察到的细胞周期效应，支持AURORA-A在DNA复制期间的重要非催化功能。AURORA-A降解在癌细胞系中诱导了猖獗的细胞凋亡，因此代表了开发新疗法以对抗AURORA-A在癌症中的功能的通用起点。
The mitotic kinase AURORA-A is essential for cell cycle progression and is considered a priority cancer target. While the catalytic activity of AURORA-A is essential for its mitotic function, recent reports indicate an additional non-catalytic function, which is difficult to target by conventional small molecules. We therefore developed a series of chemical degraders (PROTACs) by connecting a clinical kinase inhibitor of AURORA-A to E3 ligase-binding molecules (e.g. thalidomide). One degrader induced rapid, durable and highly specific degradation of AURORA-A. In addition ,we found that the degrader complex was stabilized by cooperative binding between AURORA-A and CEREBLON. Degrader-mediated AURORA-A depletion caused an S-phase defect, which is not the cell cycle effect observed upon kinase inhibition, supporting an important non-catalytic function of AURORA-A during DNA replication. AURORA-A degradation induced rampant apoptosis in cancer cell lines, and thus represents a versatile starting point for developing new therapeutics to counter AURORA-A function in cancer.
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影响因子：
16
作者：
Caudron-Herger, Maiwen;Rusin, Scott F.;Diederichs, Sven
通讯作者：
Diederichs, Sven
影响因子：
16
作者：
Baluapuri, Apoorva;Hofstetter, Julia;Wolf, Elmar
通讯作者：
Wolf, Elmar
影响因子：
4.4
作者：
Cox, Juergen;Neuhauser, Nadin;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
14.8
作者：
Bondeson DP;Mares A;Smith IE;Ko E;Campos S;Miah AH;Mulholland KE;Routly N;Buckley DL;Gustafson JL;Zinn N;Grandi P;Shimamura S;Bergamini G;Faelth-Savitski M;Bantscheff M;Cox C;Gordon DA;Willard RR;Flanagan JJ;Casillas LN;Votta BJ;den Besten W;Famm K;Kruidenier L;Carter PS;Harling JD;Churcher I;Crews CM
通讯作者：
Crews CM
影响因子：
5.8
作者：
Hochegger H;Hégarat N;Pereira-Leal JB
通讯作者：
Pereira-Leal JB