Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential.
Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential.
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DOI：
10.1073/pnas.2007328118
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发表时间：
2021-02-23
影响因子：
11.1
通讯作者：
Pan ZQ
中科院分区：
文献类型：
--
作者：
Wu K;Huynh KQ;Lu I;Moustakim M;Miao H;Yu C;Haeusgen MJ;Hopkins BD;Huang L;Zheng N;Sanchez R;DeVita RJ;Pan ZQ
Cullin-RING E3泛素连接酶（CRL）指导蛋白质降解以影响包括癌症在内的无数生理和病理过程。本工作报道了作为具有抗癌潜力的E3 CRL 4抑制剂的小分子化合物33-11和KH-4-43。这些化合物为开发工具化合物提供了机会，以解决生物化学，基于细胞和动物研究中关于CRL 4的机制和表型问题。cullin 4蛋白水平和化合物的细胞毒性反应之间的相关性研究以及cullin 4耗竭实验的结果表明，低E3丰度在使肿瘤细胞对凋亡敏感中的作用。总的来说，基于33-11/KH-4-43的CRL 4抑制剂可以提供新的可利用的治疗机会，以靶向以低CUL 4表达为特征的肿瘤系的子集。Cullin-RING（真正有趣的新基因）E3泛素连接酶（CRL）是最大的E3家族，并指导蛋白酶体降解的许多蛋白质底物，从而影响包括癌症在内的无数生理和病理过程。迄今为止，还没有报道过CRL催化活性的小分子抑制剂。在这里，我们描述了高通量筛选和药物化学优化的努力，导致两种化合物，33-11和KH-4-43，抑制E3 CRL 4和表现出抗肿瘤潜力的鉴定。这些化合物与CRL 4的核心催化复合物结合，抑制CRL 4介导的泛素化，并使细胞中CRL 4的底物CDT 1稳定。用33-11或KH-4-43在一组36个肿瘤细胞系中处理显示出细胞毒性。通过化合物抑制小鼠中人肿瘤异种移植物生长的能力验证了抗肿瘤活性。从机制上讲，化合物的细胞毒性与CDT 1的异常积累有关，CDT 1已知会引发细胞凋亡。此外，发现一个肿瘤细胞亚群表达cullin 4蛋白，其水平比其他肿瘤细胞系低70倍。低cullin 4表达的肿瘤细胞似乎表现出对33-11/KH-4-43的敏感性增加，提出了低E3丰度作为癌症易感性的作用的挑衅性假设。
Cullin-RING E3 ubiquitin ligases (CRLs) direct protein degradation to impact a myriad of physiological and pathological processes including cancer. This work reports the small-molecule compounds 33-11 and KH-4-43 as inhibitors of E3 CRL4 with anticancer potential. These compounds have provided an opportunity for developing tool compounds to address mechanistic and phenotypic questions about CRL4 in biochemical, cell-based, and animal studies. The results of correlation studies between cullin4 protein level and the compounds’ cytotoxic response as well as cullin4 depletion experiments suggest a role for low E3 abundance in sensitizing tumor cells for apoptosis. Collectively, the 33-11/KH-4-43–based CRL4 inhibitors may provide new exploitable therapeutic opportunities to target a subset of tumor lines characterized by low CUL4 expression. Cullin-RING (really intersting new gene) E3 ubiquitin ligases (CRLs) are the largest E3 family and direct numerous protein substrates for proteasomal degradation, thereby impacting a myriad of physiological and pathological processes including cancer. To date, there are no reported small-molecule inhibitors of the catalytic activity of CRLs. Here, we describe high-throughput screening and medicinal chemistry optimization efforts that led to the identification of two compounds, 33-11 and KH-4-43, which inhibit E3 CRL4 and exhibit antitumor potential. These compounds bind to CRL4’s core catalytic complex, inhibit CRL4-mediated ubiquitination, and cause stabilization of CRL4’s substrate CDT1 in cells. Treatment with 33-11 or KH-4-43 in a panel of 36 tumor cell lines revealed cytotoxicity. The antitumor activity was validated by the ability of the compounds to suppress the growth of human tumor xenografts in mice. Mechanistically, the compounds’ cytotoxicity was linked to aberrant accumulation of CDT1 that is known to trigger apoptosis. Moreover, a subset of tumor cells was found to express cullin4 proteins at levels as much as 70-fold lower than those in other tumor lines. The low-cullin4–expressing tumor cells appeared to exhibit increased sensitivity to 33-11/KH-4-43, raising a provocative hypothesis for the role of low E3 abundance as a cancer vulnerability.
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影响因子：
14.8
作者：
Arrowsmith CH;Audia JE;Austin C;Baell J;Bennett J;Blagg J;Bountra C;Brennan PE;Brown PJ;Bunnage ME;Buser-Doepner C;Campbell RM;Carter AJ;Cohen P;Copeland RA;Cravatt B;Dahlin JL;Dhanak D;Edwards AM;Frederiksen M;Frye SV;Gray N;Grimshaw CE;Hepworth D;Howe T;Huber KV;Jin J;Knapp S;Kotz JD;Kruger RG;Lowe D;Mader MM;Marsden B;Mueller-Fahrnow A;Müller S;O'Hagan RC;Overington JP;Owen DR;Rosenberg SH;Roth B;Ross R;Schapira M;Schreiber SL;Shoichet B;Sundström M;Superti-Furga G;Taunton J;Toledo-Sherman L;Walpole C;Walters MA;Willson TM;Workman P;Young RN;Zuercher WJ
通讯作者：
Zuercher WJ
影响因子：
64.5
作者：
Duda, David M.;Borg, Laura A.;Scott, Daniel C.;Hunt, Harold W.;Hammel, Michal;Schulman, Brenda A.
通讯作者：
Schulman, Brenda A.
影响因子：
16
作者：
Reichermeier, Kurt M.;Straube, Ronny;Kirkpatrick, Donald S.
通讯作者：
Kirkpatrick, Donald S.
影响因子：
4.8
作者：
Seidel, Susanne A. I.;Dijkman, Patricia M.;Lea, Wendy A.;van den Bogaart, Geert;Jerabek-Willemsen, Moran;Lazic, Ana;Joseph, Jeremiah S.;Srinivasan, Prakash;Baaske, Philipp;Simeonov, Anton;Katritch, Ilia;Melo, Fernando A.;Ladbury, John E.;Schreiber, Gideon;Watts, Anthony;Braun, Dieter;Duhr, Stefan
通讯作者：
Duhr, Stefan
影响因子：
20.3
作者：
Sievers, Quinlan L.;Gasser, Jessica A.;Ebert, Benjamin L.
通讯作者：
Ebert, Benjamin L.