Impact of Target Warhead and Linkage Vector on Inducing Protein Degradation: Comparison of Bromodomain and Extra-Terminal (BET) Degraders Derived from Triazolodiazepine (JQ1) and Tetrahydroquinoline (I-BET726) BET Inhibitor Scaffolds.
Impact of Target Warhead and Linkage Vector on Inducing Protein Degradation: Comparison of Bromodomain and Extra-Terminal (BET) Degraders Derived from Triazolodiazepine (JQ1) and Tetrahydroquinoline (I-BET726) BET Inhibitor Scaffolds.
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DOI：
10.1021/acs.jmedchem.6b01912
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发表时间：
2018-01-25
影响因子：
7.3
通讯作者：
Ciulli A
中科院分区：
文献类型：
--
作者：
Chan KH;Zengerle M;Testa A;Ciulli A
蛋白水解靶向嵌合体（PROTAC）的设计是用于诱导蛋白质降解的强有力的小分子方法。PROTAC通过接头将靶弹头缀合至E3泛素连接酶配体。在这里，我们研究了使用不同的聚乙二醇连接体与VHL配体VH 032通过不同的出口载体衍生化两种不同的BET溴结构域抑制剂三唑并二氮杂卓JQ 1和更有效的四氢喹啉I-BET 726的影响。三唑并二氮杂卓PROTAC表现出三元复合物形成的正协同作用，并且是比四氢喹啉化合物更有效的降解剂，而四氢喹啉化合物则表现出负协同作用。在急性髓性白血病细胞系中观察到BET降解和cMyc驱动的抗增殖活性对接头长度的显著依赖性。这项工作作为一个警示故事，说明了更有效的抑制剂不一定会产生更有效的PROTAC，并强调了缀合所起的关键作用。所提供的见解和框架的二价降解剂的结构-活性关系，预计有广泛的未来适用性。
The design of proteolysis-targeting chimeras (PROTACs) is a powerful small-molecule approach for inducing protein degradation. PROTACs conjugate a target warhead to an E3 ubiquitin ligase ligand via a linker. Here we examined the impact of derivatizing two different BET bromodomain inhibitors, triazolodiazepine JQ1 and the more potent tetrahydroquinoline I-BET726, via distinct exit vectors, using different polyethylene glycol linkers to VHL ligand VH032. Triazolodiazepine PROTACs exhibited positive cooperativities of ternary complex formation and were more potent degraders than tetrahydroquinoline compounds, which showed negative cooperativities instead. Marked dependency on linker length was observed for BET-degrading and cMyc-driven antiproliferative activities in acute myeloid leukemia cell lines. This work exemplifies as a cautionary tale how a more potent inhibitor does not necessarily generate more potent PROTACs and underscores the key roles played by the conjugation. The provided insights and framework for structure–activity relationships of bivalent degraders are anticipated to have wide future applicability.
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DOI：
10.1126/science.1249830
发表时间：
2014-10-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baud MGJ;Lin-Shiao E;Cardote T;Tallant C;Pschibul A;Chan KH;Zengerle M;Garcia JR;Kwan TT;Ferguson FM;Ciulli A
通讯作者：
Ciulli A
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.4
作者：
Lopez-Girona, A.;Mendy, D.;Ito, T.;Miller, K.;Gandhi, A. K.;Kang, J.;Karasawa, S.;Carmel, G.;Jackson, P.;Abbasian, M.;Mahmoudi, A.;Cathers, B.;Rychak, E.;Gaidarova, S.;Chen, R.;Schafer, P. H.;Handa, H.;Daniel, T. O.;Evans, J. F.;Chopra, R.
通讯作者：
Chopra, R.
影响因子：
4
作者：
Ottis, Philipp;Crews, Craig M.
通讯作者：
Crews, Craig M.
影响因子：
15
作者：
Schneekloth, JS;Fonseca, FN;Crews, CM
通讯作者：
Crews, CM