Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases.
Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases.
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对不同肿瘤类型的分析建立了基于VHL的ProTaC的广泛用途，并对候选泛素连接酶进行了分类。
DOI：
10.1016/j.isci.2022.103985
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发表时间：
2022-03-18
期刊：
影响因子：
5.8
通讯作者：
Mohl D
中科院分区：
文献类型：
--
作者：
Luo X;Archibeque I;Dellamaggiore K;Smither K;Homann O;Lipford JR;Mohl D
促进关键癌症靶标降解的小分子治疗剂的成功推动了用称为PROTAC（蛋白水解靶向嵌合体）的双特异性分子模拟这种活性的强烈努力。PROTAC与连接酶和靶标的同时结合可以诱导邻近驱动的泛素化和降解。VHL和CRBN是两种最具特征的PROTAC连接酶，但支配其细胞活性的规则仍不清楚。为了建立这些要求并将其扩展到新的连接酶，我们筛选了一组56个细胞系，这些细胞系具有两种有效的PROTAC，它们利用VHL、MZ 1或CRBN、dBET 1诱导BRD 4的降解。除了明显的例外，MZ 1在面板中广泛活跃，而dBET 1经常不活跃。对PROTAC活性的预测性生物标志物的搜索发现，VHL和CRBN的表达和突变本身是细胞系组中PROTAC活性的预测因子。不同肿瘤类型的特征分析确立了基于VHL的PROTAC的广泛用途CRBN依赖性dBET 1活性在癌细胞系中经常受到抑制拷贝丢失和mRNA表达预测VHL和CRBN依赖性PROTAC的活性生物工程;癌症;分子生物学
The success of small molecule therapeutics that promotes degradation of critical cancer targets has fueled an intense effort to mimic this activity with bispecific molecules called PROTACs (proteolysis targeting chimeras). The simultaneous binding of PROTACs to a ligase and target can induce proximity-driven ubiquitination and degradation. VHL and CRBN are the two best characterized PROTAC ligases, but the rules governing their cellular activities remain unclear. To establish these requirements and extend them to new ligases, we screened a panel of 56 cell lines with two potent PROTACs that utilized VHL, MZ1, or CRBN, dBET1 to induce degradation of BRD4. With notable exceptions, MZ1 was broadly active in the panel whereas dBET1 was frequently inactive. A search for predictive biomarkers of PROTAC activity found that expression and mutation of VHL and CRBN were themselves predictors of PROTAC activity in the cell line panel. Profiling of diverse tumor types establishes the broad utility of VHL-based PROTACs CRBN-dependent dBET1 activity is frequently suppressed in cancer cell lines Copy loss and mRNA expression predict the activity of VHL and CRBN-dependent PROTACs Bioengineering; Cancer; Molecular biology
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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：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
56.9
作者：
Han, Ting;Goralski, Maria;Nijhawan, Deepak
通讯作者：
Nijhawan, Deepak
影响因子：
7.3
作者：
Hansen, Joshua D.;Condroski, Kevin;Lu, Chin-Chun
通讯作者：
Lu, Chin-Chun
影响因子：
11.2
作者：
Malyukova, Alena;Dohda, Takeaki;Sangfelt, Olle
通讯作者：
Sangfelt, Olle