A Temporal PROTAC Cocktail-Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells.
A Temporal PROTAC Cocktail-Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells.
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时间 PROTAC 鸡尾酒——介导的 AURKA 顺序降解消除了急性髓系白血病干细胞
DOI：
10.1002/advs.202104823
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发表时间：
2022-08
期刊：
影响因子：
15.1
通讯作者：
Liu, Quentin
中科院分区：
文献类型：
--
作者：
Liu, Fang;Wang, Xuan;Duan, Jianli;Hou, Zhijie;Wu, Zhouming;Liu, Lingling;Lei, Hanqi;Huang, Dan;Ren, Yifei;Wang, Yue;Li, Xinyan;Zhuo, Junxiao;Zhang, Zijian;He, Bin;Yan, Min;Yuan, Huiming;Zhang, Lihua;Yan, Jinsong;Wen, Shijun;Wang, Zifeng;Liu, Quentin
AURKA在多种恶性肿瘤中是一个潜在的激酶靶点。这些不依赖于激酶的致癌功能部分揭示了在III期临床试验中激酶抑制剂的不充分疗效。同时靶向AURKA的催化和非催化功能可能是一种可行的方法。在这里，我们开发了一套针对嵌合体的AURKA蛋白水解酶(PROTAC)。基于CRBN的dAurA383优先降解高丰度的有丝分裂AURKA，而基于CIAP的dAurA450优先降解急性髓系白血病(AML)细胞中低丰度的间期AURKA。蛋白质组学和转录组分析表明，dAurA383启动了“有丝分裂细胞周期”和“干细胞”过程，而dAurA450则抑制了“MYC/E2F靶点”和“干细胞”过程。DAurA383和dAurA450组合为PROTAC鸡尾酒。该鸡尾酒有效地降解AURKA，缓解挂钩效应，并协同抑制AML干细胞。此外，PROTAC鸡尾酒在异种移植小鼠模型和原发患者骨髓细胞中诱导AML消退。这些发现确立了PROTAC鸡尾酒作为一种有前景的时空给药策略，以顺序消除癌蛋白的多方面功能，缓解挂钩效应，并防止癌症干细胞介导的耐药性。本研究建立了基于CRBN的dAurA383和基于CIAP的dAurA450的PROTAC鸡尾酒，作为一种有前景的时空给药策略，以顺序消除有丝分裂AURKA和间期AURKA的多方面功能，缓解挂钩效应，防止肿瘤干细胞介导的耐药。PROTAC鸡尾酒战略被提出为第二代PROTAC。
AURKA is a potential kinase target in various malignancies. The kinase‐independent oncogenic functions partially disclose the inadequate efficacy of the kinase inhibitor in a Phase III clinical trial. Simultaneously targeting the catalytic and noncatalytic functions of AURKA may be a feasible approach. Here, a set of AURKA proteolysis targeting chimeras (PROTACs) are developed. The CRBN‐based dAurA383 preferentially degrades the highly abundant mitotic AURKA, while cIAP‐based dAurA450 degrades the lowly abundant interphase AURKA in acute myeloid leukemia (AML) cells. The proteomic and transcriptomic analyses indicate that dAurA383 triggers the “mitotic cell cycle” and “stem cell” processes, while dAurA450 inhibits the “MYC/E2F targets” and “stem cell” processes. dAurA383 and dAurA450 are combined as a PROTAC cocktail. The cocktail effectively degrades AURKA, relieves the hook effect, and synergistically inhibits AML stem cells. Furthermore, the PROTAC cocktail induces AML regression in a xenograft mouse model and primary patient blasts. These findings establish the PROTAC cocktail as a promising spatial‐temporal drug administration strategy to sequentially eliminate the multifaceted functions of oncoproteins, relieve the hook effect, and prevent cancer stem cell‐mediated drug resistance. This study establishes the PROTAC cocktail of CRBN‐based dAurA383 and cIAP‐based dAurA450 as a promising spatial‐temporal drug administration strategy to sequentially eliminate the multifaceted functions of mitotic AURKA and interphase AURKA, relieve the hook effect, and prevent cancer stem cell‐mediated drug resistance in acute myeloid leukemia. PROTAC cocktail strategy is proposed to be a second generation of PROTACs.
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影响因子：
14.8
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
通讯作者：
Wolf E
DOI：
10.1007/978-1-61779-080-5_34
发表时间：
2011-01-01
期刊：
CANCER CELL CULTURE: METHODS AND PROTOCOLS, SECOND EDITION
影响因子：
--
作者：
Bijnsdorp, Irene V.;Giovannetti, Elisa;Peters, Godefridus J.
通讯作者：
Peters, Godefridus J.
影响因子：
14.9
作者：
Burley SK;Bhikadiya C;Bi C;Bittrich S;Chen L;Crichlow GV;Christie CH;Dalenberg K;Di Costanzo L;Duarte JM;Dutta S;Feng Z;Ganesan S;Goodsell DS;Ghosh S;Green RK;Guranović V;Guzenko D;Hudson BP;Lawson CL;Liang Y;Lowe R;Namkoong H;Peisach E;Persikova I;Randle C;Rose A;Rose Y;Sali A;Segura J;Sekharan M;Shao C;Tao YP;Voigt M;Westbrook JD;Young JY;Zardecki C;Zhuravleva M
通讯作者：
Zhuravleva M
影响因子：
4.7
作者：
Ewart-Toland, A;Dai, Q;Balmain, A
通讯作者：
Balmain, A
影响因子：
11.2
作者：
LeRoy, Patrick J.;Hunter, John J.;Ecsedy, Jeffrey A.
通讯作者：
Ecsedy, Jeffrey A.