Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth.
Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth.
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DOI：
10.1038/s41589-021-00813-7
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发表时间：
2021-10
影响因子：
14.8
通讯作者：
Rosen, Neal
中科院分区：
文献类型：
--
作者：
Lee, Bianca J.;Boyer, Jacob A.;Burnett, G. Leslie;Thottumkara, Arun P.;Tibrewal, Nidhi;Wilson, Stacy L.;Hsieh, Tientien;Marquez, Abby;Lorenzana, Edward G.;Evans, James W.;Hulea, Laura;Kiss, Gert;Liu, Hui;Lee, Dong;Larsson, Ola;McLaughlan, Shannon;Topisirovic, Ivan;Wang, Zhengping;Wang, Zhican;Zhao, Yongyuan;Wildes, David;Aggen, James B.;Singh, Mallika;Gill, Adrian L.;Smith, Jacqueline A. M.;Rosen, Neal
pan-mTOR活性位点抑制剂的临床益处受到毒性和受体表达反馈抑制缓解的限制。为了解决这些限制，我们设计了一系列选择性抑制mTORC 1而不是mTORC 2的化合物。这些“双空间抑制剂”包含与mTOR活性位点抑制剂共价连接的雷帕霉素样核心部分。这些组分的结构修饰调节了它们对mTOR上的结合位点的亲和力和双空间化合物的选择性。mTORC 1选择性化合物有效抑制4 EBP 1磷酸化并导致乳腺癌异种移植物消退。抑制4 EBP 1磷酸化足以阻断癌细胞生长，并且是最大抗肿瘤活性所必需的。在mTORC 1选择性剂量下，这些化合物不会改变葡萄糖耐量，也不会缓解HER 3的AKT依赖性反馈抑制。因此，在临床前模型中，与泛mTOR抑制剂相比，mTORC 1的选择性抑制剂有效地抑制肿瘤生长，同时引起更少的毒性和受体再活化。
The clinical benefits of pan-mTOR active-site inhibitors are limited by toxicity and relief of feedback inhibition of receptor expression. To address these limitations, we designed a series of compounds that selectively inhibit mTORC1 and not mTORC2. These `bi-steric inhibitors’ comprise a rapamycin-like core moiety covalently linked to an mTOR active-site inhibitor. Structural modification of these components modulated their affinities for their binding sites on mTOR and the selectivity of the bi-steric compound. mTORC1-selective compounds potently inhibited 4EBP1 phosphorylation and caused regressions of breast cancer xenografts. Inhibition of 4EBP1 phosphorylation was sufficient to block cancer cell growth and was necessary for maximal antitumor activity. At mTORC1-selective doses, these compounds do not alter glucose tolerance, nor do they relieve AKT-dependent feedback inhibition of HER3. Thus, in preclinical models, selective inhibitors of mTORC1 potently inhibit tumor growth while causing less toxicity and receptor reactivation as compared to pan-mTOR inhibitors.
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影响因子：
29
作者：
Hagiwara, Asami;Cornu, Marion;Hall, Michael N.
通讯作者：
Hall, Michael N.
影响因子：
5.3
作者：
Fingar, DC;Richardson, CJ;Blenis, J
通讯作者：
Blenis, J
影响因子：
--
作者：
LUENGO, JI;YAMASHITA, DS;HOLT, DA
通讯作者：
HOLT, DA
影响因子：
7
作者：
Cenik C;Cenik ES;Byeon GW;Grubert F;Candille SI;Spacek D;Alsallakh B;Tilgner H;Araya CL;Tang H;Ricci E;Snyder MP
通讯作者：
Snyder MP
影响因子：
--
作者：
Buti S;Leonetti A;Dallatomasina A;Bersanelli M
通讯作者：
Bersanelli M